F-box proteiinien assosioituminen syöpään

Nat Rev Cancer. 2014 Apr;14(4):233-47. doi: 10.1038/nrc3700.

Roles of F-box proteins in cancer.

Wang Z¹, Liu P², Inuzuka H³, Wei W³.

Abstract

F-box proteins, which are the substrate-recognition subunits of SKP1-cullin 1-F-box protein (SCF) E3 ligase complexes, have pivotal roles in multiple cellular processes through ubiquitylation and subsequent degradation of target proteins. Dysregulation of F-box protein-mediated proteolysis leads to human malignancies. Notably, inhibitors that target F-box proteins have shown promising therapeutic potential, urging us to review the current understanding of how F-box proteins contribute to tumorigenesis. As the physiological functions for many of the 69 putative F-box proteins remain elusive, additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F-box protein-targeted anticancer therapies.

PMID:

24658274

PMCID:

PMC4306233

DOI:

10.1038/nrc3700

[Indexed for MEDLINE]

Free PMC Article

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Figure 1

Illustration of functional domains in the highlighted F-Box proteins, grouped by their potential functions in cancer that have been shown by available mouse models

On the basis of data from mouse genetics, pathological profiles and biochemical substrates identified for each F-box protein we group F-box proteins into four categories to indicate their roles in tumorigenesis: tumour suppressor (part a), oncogene (part b), context-dependent (part c) and undetermined (part d).

 β-TRCP, β-transducin repeat-containing protein; 

BH, β-helix;

 F, F-box motif;

 FBXL, F-box and leucine-rich repeat protein; 

FBXO, F-box only; 

FBXW, F-box/WD repeat-containing protein; 

HT, hemerythrin domain;

 IBR, in between ring fingers domain;

 L, leucine-rich repeat;

 Nop14, NOP14-like family domain;

 NosD, periplasmic copper-binding protein; 

PI31-prot-N, PI31 proteasome regulator amino-terminal domain; 

SKP2, S-phase kinase-associated protein 2; 

SPRY, SPLA and the ryanodine receptor domain; 

T, transmembrane region; Tr, D domain of β-TRCP; 

TRP, tetratricopeptide repeat; 

UH, UvrD/REP helicase N-terminal domain; 

UvrD, UvrD-like helicase C-terminal domain;

 W, WD40 repeat;

 Zu, putative zinc finger in N-recognin.

Artikkeli animaalisista BTB/Kelch proteiineista . Kelch toiston omaavan superperheen fylogeniaa.

BMC Bioinformatics
December 2003, 4:42 | Cite as
Molecular phylogeny of the kelch-repeat superfamily reveals an expansion of BTB/kelch proteins in animals Authors Soren Prag, Josephine C Adams, .Dept. of Cell Biology, Lerner Research InstituteCleveland Clinic FoundationClevelandUSA
Open Access
Research article

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Abstract. Background

The kelch motif is an ancient and evolutionarily-widespread sequence motif of 44–56 amino acids in length. It occurs as five to seven repeats that form a β-propeller tertiary structure. Over 28 kelch-repeat proteins have been sequenced  (2003) and functionally characterised from diverse organisms spanning from viruses, plants and fungi to mammals and it is evident from expressed sequence tag, domain and genome databases that many additional hypothetical proteins contain kelch-repeats. In general, kelch-repeat β-propellers are involved in protein-protein interactions, however the modest sequence identity between kelch motifs, the diversity of domain architectures, and the partial information on this protein family in any single species, all present difficulties to developing a coherent view of the kelch-repeat domain and the kelch-repeat protein superfamily. To understand the complexity of this superfamily of proteins, we have analysed by bioinformatics the complement of kelch-repeat proteins encoded in the human genome and have made comparisons to the kelch-repeat proteins encoded in other sequenced genomes.

Results  We identified 71 kelch-repeat proteins encoded in the human genome, whereas 5 or 8 members were identified in yeasts and around 18 in C. elegans, D. melanogaster and A. gambiae. Multiple domain architectures were identified in each organism, including previously unrecognised forms. The vast majority of kelch-repeat domains are predicted to form six-bladed β-propellers. The most prevalent domain architecture in the metazoan animal genomes studied was the BTB/kelch domain organisation and we uncovered 3 subgroups of human BTB/kelch proteins. Sequence analysis of the kelch-repeat domains of the most robustly-related subgroups identified differences in β-propeller organisation that could provide direction for experimental study of protein-binding characteristics.

Conclusion The kelch-repeat superfamily constitutes a distinct and evolutionarily-widespread family of β-propeller domain-containing proteins. Expansion of the family during the evolution of multicellular animals is mainly accounted for by a major expansion of the BTB/kelch domain architecture. BTB/kelch proteins constitute 72 % of the kelch-repeat superfamily of H. sapiens and form three subgroups, one of which appears the most-conserved during evolution. Distinctions in propeller blade organisation between subgroups 1 and 2 were identified that could provide new direction for biochemical and functional studies of novel kelch-repeat proteins.

Keywords

Domain Architecture Galactose Oxidase Biology Workbench Eucaryotic Organism Identity Consensus Sequence 

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

BLAST

basic local alignment search tool

BTB/POZ

Broad-Complex, Tramtrack, and Bric-a-Brac/ Poxvirus and Zincfinger domain

CDD

conserved domain database

EST

expressed sequence tag

ORF

open reading frame, Pfam, Protein families database of alignments and HMMs

SMART

simple modular architecture research tool.

Electronic supplementary material

The online version of this article (doi: 10.1186/1471-2105-4-42) contains supplementary material, which is available to authorized users.

Background

The kelch motif is an ancient and evolutionarily-widespread sequence motif of 44–56 amino acids in length. Eight residues within the motif are highly-conserved and constitute a consensus sequence [1, 2, 3] (Fig. 1A). Kelch motifs occur as groups of five to seven repeats and have been identified in proteins of otherwise distinct molecular architecture, termed the kelch-repeat superfamily. Currently, over 28 kelch-repeat proteins have been sequenced and functionally characterised in diverse organisms including viruses, plants, fungi and mammals [3]. Several kelch repeat-containing proteins have been recognised in Bacteria and Archaea (GenBank NP_713516, NP_639451 and Pfam01344 species distribution link), revealing the universal nature of the repeats. On the basis of the crystal structure determined for a single kelch-repeat protein, Hypomyces rosellus galactose oxidase (PDB 1GOF), the sets of repeated kelch motifs are predicated to form a β-propeller structure [2, 4].

The kelch motif and the β-propeller fold. A, Consensus sequence of the kelch motif. Compiled from [2] and [3]. The sequence motif is shown in relation to the four β-sheets of a propeller blade structure, as determined for the kelch motifs of fungal galactose oxidase [4]. In the consensus, G= glycine, Y = tyrosine, W = tryptophan, s = small residue; l = large residue; h = hydrophobic residue. B, Structure of a kelch-repeat propeller blade. A single blade from the crystal structure of fungal galactose oxidase (1GOF) is shown. β sheets 1–4 are colored as in panel A. The N- and C-termini join to adjacent blades. As indicated by the mapping of the consensus amino acids onto the blade, the most highly-conserved residues are located in the β-sheets. In various examples of β-propeller proteins, the intra- and inter-blade loops have variable sequences and contribute to protein-protein interactions [3]. C, Structure of the kelch-repeat β-propeller domain of fungal galactose oxidase (1GOF). β-sheets 1–4 in each blade are colored as in panel A. As indicated, this β-propeller contains seven blades. The β-4 strand of blade 7 is derived from the amino-terminus of the domain and thus closes the circular structure.

The β-propeller is a widespread and universal protein domain fold, as revealed from crystal structures of diverse proteins [5, 6, 7]. Many unrelated primary sequences can adopt the stereotypical topology of a β-propeller; however, several sequence repeat motifs have been identified in relation to known crystal structures that are predictors of propeller domains. These include the WD motif, the regulator of chromosome condensation 1 (RCC1) motif and the tachylectin-2 repeat, as well as the kelch motif [3, 5, 6, 7, 8, 9]. Each "blade" of a β-propeller structure is formed from a four-stranded antiparallel twisted β-sheet fold, in which each β-sheet packs onto the adjoining sheets through hydrophobic contacts (Fig. 1B). Four to eight of these β-sheet modules are radially arranged around a central axis to form the β-propeller domain, with the twist of the β-sheets within each module producing the propeller-blade appearance (Fig. 1C). Intra- and inter-blade loops of varying lengths protrude above, below, or at the sides of the β-sheets and contribute variability to the binding properties of individual β-propellers [3, 5, 6] (Fig. 1B). The whole structure is closed and stabilised by interactions between the first and last blades. In the four-bladed β-propellers of hemopexin and collagenase this is achieved by disulphide bonding between the first and last blades [10, 11]. In the other examples for which there is crystal structural information, the last blade of the β-propeller is assembled as a composite from sequences at the amino- and carboxy-terminal ends of the domain, that are held together by hydrogen bonds [3, 5, 6, 9] (example of galactose oxidase shown in Fig. 1C).

Kelch-repeat β-propellers undergo a variety of binding interactions with other molecules. Several kelch proteins, including D. melanogaster kelch and mammalian IPP, bind and cross-link F-actin through the β-propeller domain [12, 13]. In contrast, the kelch repeats of other proteins, such as gigaxonin, Keap1, or recombination-activating gene 2, (RAG-2), have unique binding partner proteins [14, 15, 16] and the β-propeller of fungal galactose oxidase corresponds to the catalytic domain of the enzyme [2, 4]. The kelch-repeat β-propeller is thus considered to form a general protein-protein interaction module that associates with diverse and specific binding partners [3]. Several kelch-repeat proteins contain other protein domains, of particular note being the Broad-Complex, Tramtrack, and Bric-a-Brac/Poxvirus and Zincfinger (BTB/POZ) domain (CDD6184, Pfam 00651, SMART0225) [1, 3, 17]. The BTB/POZ domain was first identified as a dimerisation domain of transcription factors and also mediates homodimerisation of kelch and other BTB/kelch domain proteins [10, 17, 18].

As summarised above, the current view of the kelch-repeat superfamily has been compiled from studies of individual kelch-repeat proteins from diverse organisms. The extent and complexity of the kelch-repeat family within an individual species is unknown. An overview of this domain family would be of value in order to make a rational assignment of structural subgroups and to develop a coherent perspective on the evolution of this protein domain between modern organisms. A clear view of kelch-repeat proteins could also open up new possibilities for sequence analysis, prediction and experimental analysis of structure/function relationships, and a greater understanding of the specific properties of kelch-repeat proteins within the large β-propeller fold group. In modern life sciences, such molecular information provides a fundamental context for well-targeted biochemical and biological studies of individual proteins. Building on the availability of complete genome sequence information for H. sapiens, D. melanogaster, A. gambiae, C. elegans, S. cerevisiae, S. pombe and A. thaliana we have addressed these questions through database mining and bioinformatic sequence analyses.

Results

ATRN (20p13), MGCA, DPPT-L, Attractiini

https://www.ncbi.nlm.nih.gov/gene/8455

Official Full Name

attractinAlso known as

MGCA; DPPT-L

Summary

This gene encodes both membrane-bound and secreted protein isoforms. A membrane-bound isoform exhibits sequence similarity with the mouse mahogany protein, a receptor involved in controlling obesity. A secreted isoform is involved in the initial immune cell clustering during inflammatory responses that may regulate the chemotactic activity of chemokines. [provided by RefSeq, Apr 2016]

Expression

Ubiquitous expression in duodenum (RPKM 20.8), thyroid (RPKM 17.2) and 25 other tissues See more

Tietoa MEGF8 geenin taustasta

Other Names for This Gene

• C19orf49
• EGF-like domain-containing protein 4
• EGF-like-domain, multiple 4
• EGFL4
• epidermal growth factor-like protein 4
• FLJ22365
• HBV pre-s2 binding protein 1
• MEGF8_HUMAN
• multiple EGF-like-domains 8
• multiple epidermal growth factor-like domains protein 8
• SBP1

https://www.researchgate.net/publication/24011705_Massively_parallel_sequencing_identifies_the_gene_Megf8_with_ENU-induced_mutation_causing_heterotaxy

Abstract

Forward genetic screens with ENU (N-ethyl-N-nitrosourea) mutagenesis can facilitate gene discovery, but mutation identification is often difficult. We present the first study in which an ENU-induced mutation was identified by massively parallel DNA sequencing. This mutation causes heterotaxy and complex congenital heart defects and was mapped to a 2.2-Mb interval on mouse chromosome 7. Massively parallel sequencing of the entire 2.2-Mb interval identified 2 single-base substitutions, one in an intergenic region and a second causing replacement of a highly conserved cysteine with arginine (C193R) in the gene Megf8. Megf8 is evolutionarily conserved from human to fruit fly, and is observed to be ubiquitously expressed. Morpholino knockdown of Megf8 in zebrafish embryos resulted in a high incidence of heterotaxy, indicating a conserved role in laterality specification. Megf8(C193R) mouse mutants show normal breaking of symmetry at the node, but Nodal signaling failed to be propagated to the left lateral plate mesoderm. Videomicroscopy showed nodal cilia motility, which is required for left-right patterning, is unaffected. Although this protein is predicted to have receptor function based on its amino acid sequence, surprisingly confocal imaging showed it is translocated into the nucleus, where it is colocalized with Gfi1b and Baf60C, two proteins involved in chromatin remodeling. Overall, through the recovery of an ENU-induced mutation, we uncovered Megf8 as an essential regulator of left-right patterning.

 https://link.springer.com/article/10.1186/1471-2105-4-42 
Tästä saa fylogeneettisen tiedon. BTB Kelch domeeniproteiineista.


(https://ghr.nlm.nih.gov/gene/MEGF8 
Uusimpia artikkeleita lokakuulta 2019)

Normal Function

The MEGF8 gene provides instructions for making a protein whose function is unclear. Based on its structure, the Megf8 protein may be involved in cell processes such as attaching cells to one another (cell adhesion) and helping proteins interact with each other. Researchers also suspect that the Megf8 protein plays a role in the normal shaping (patterning) of many parts of the body during embryonic development.

Other Names for This Gene

• C19orf49
• EGF-like domain-containing protein 4
• EGF-like-domain, multiple 4
• EGFL4
• epidermal growth factor-like protein 4
• FLJ22365
• HBV pre-s2 binding protein 1
• MEGF8_HUMAN
• multiple EGF-like-domains 8
• multiple epidermal growth factor-like domains protein 8
• SBP1

MEGF8 (19q13.2) , 12 kelch-toistoa, monta EGF-kaltaista domaania, ec domaanin CUB , plasmod Pvs28 ja vWFA domaanit omaava iso proteiini

https://www.ncbi.nlm.nih.gov/gene/1954
(En ole tavannut aiemmin sellaista proteiinia tästä  Kelch-superperheestä, jossa olisi näin monta kelch-toistoa(12).  Onkohan se geenirekombinaatio  jokin hybridi fylogeneettisesti kun siinä on kahden  Kelch-proteiini verran kelch-domeeneja ? Katson jos löydän fylogeneettistä tietoa)

Peptidisekvenssi on 2845 aa.  Proteiinilla on extrasellulaarinen CUB-domeeni (a.a. 49-1399 , N terminaalin lähellä. Transmembraaninen jakso on C-terminaalissa (2648-2845 a.a.)  EGF-kaltaisia domeeneja on useita. Löytyy myös PSI,  plexiinitoisto (A.A. 950- 988)  ja Plasmod-Pvs28 domeeni (a.a. 2189-2314 ) (plasmodium ookineetin pintaproteiini, jonka kaltaisesta on  kehitelty  rokotetta plasmodium vivaxtyyppiä vastaan). Sitten löytyy von Willebrand faktoriA- tyyppinen domeeni, jonka kaltaista alunperin havaittiin  hyytymistekijöistä.
 Kelch-toistot  kelch-3 ja Kelch neljä ovat  galaktoosioksidaasidomeeneja.
Geeniä ilmenee  runsaiten aivossa ja rasvakudoksessa. Sen puutteet  tunnetaan kliinisenä  oireyhtymänä Carpenter syndroma 2:na,  jossa on mm.  kehon lateralisaatiomallin  muuttumisia,kuten sydän oikealla puolella.https://www.norio-keskus.fi/tietoa/diagnoosikohtaista-tietoa/carpenterin-oireyhtyma.html
Carpenterin oireyhtymätyyppi 1:n geneettinen poikkeavuus on paikannettu kromosomiin 6 (6p12.1-p11.2), RAB23-nimiseen geeniin. Carpenterin oireyhtymän tyyppi 2 aiheutuu puolestaan MEGF8-geenin mutaatiosta kromosomissa 19 (19q13.2).
Molemmat Carpenterin oireyhtymätyypit noudattavat autosomissa resessiivistä eli peittyvää periytymistapaa.
Carpenterin oireyhtymän tyyppi 1 on yleisempi kuin tyyppi 2. Carpenterin oireyhtymän kokonaisesiintyvyydeksi on arvioitu 1 : 1 000 000. Lääketieteellinen kirjallisuus kuvaa yli 70 potilasta. Kaikissa tapauksissa vanhemmat ovat olleet terveitä, mikä viittaa oireyhtymän syntyneen biologisesti sattumalta, aivan uuden, nk. de novo-mutaation seurauksesta. De novo-mutaatiot saavat alkunsa hedelmöitykseen osallistuvan sukusolun, munasolun tai siittiön, kypsyessä tai alkion varhaisten solunjakautumisten yhteydessä pian hedelmöityksen jälkeen.

Official Full Name

multiple EGF like domains 8

Also known as

SBP1; CRPT2; EGFL4; C19orf49
CRPT2 ( Carpenter syndrome 2)

Summary

The protein encoded by this gene is a single-pass type I membrane protein of unknown function that contains several EGF-like domains, Kelch repeats, and PSI domains. Defects in this gene are a cause of Carpenter syndrome 2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

Expression

Ubiquitous expression in brain (RPKM 10.9), fat (RPKM 6.9) and 25 other tissues See more

Preferred Names

multiple epidermal growth factor-like domains protein 8

Names

EGF-like domain-containing protein 4

EGF-like-domain, multiple 4

HBV pre-S2-binding protein 1

HBV pre-s2 binding protein 1

epidermal growth factor-like protein 4

hepatitis B virus pre-S2-binding protein 1

.

1. [Screening of the genes of hepatitis B virus PreS2 interacting proteins]. Lu YY, et al. Zhonghua Gan Zang Bing Za Zhi, 2003 Jan. PMID 12546731
2. Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization. Twigg SR, et al. Am J Hum Genet, 2012 Nov 2. PMID 23063620, Free PMC Article
3. Identification of high-molecular-weight proteins with multiple EGF-like motifs by motif-trap screening. Nakayama M, et al. Genomics, 1998 Jul 1. PMID 9693030
4. Role of the E3 ubiquitin ligase RNF157 as a novel downstream effector linking PI3K and MAPK signaling pathways to the cell cycle. Dogan T, et al. J Biol Chem, 2017 Sep 1. PMID 28655764, Free PMC Article
5. Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia. Kahle JJ, et al. Hum Mol Genet, 2011 Feb 1. PMID 21078624, Free PMC Article

See all (19) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. mutations in MEGF8 cause a Carpenter syndrome subtype frequently associated with defective left-right patterning, probably through perturbation of signaling by hedgehog and nodal family members.

 NP_001258867.1  multiple epidermal growth factor-like domains protein 8 isoform 1 precursor
See identical proteins and their annotated locations for NP_001258867.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1).

Conserved Domains (9) summary

cd00041
Location:49 → 139

CUB; CUB domain; extracellular domain; present in proteins mostly known to be involved in development; not found in prokaryotes, plants and yeast.

cd00055
Location:1210 → 1259

EGF_Lam; Laminin-type epidermal growth factor-like domain; laminins are the major noncollagenous components of basement membranes that mediate cell adhesion, growth migration, and differentiation; the laminin-type epidermal growth factor-like module occurs in ...

sd00038
Location:228 → 275

Kelch; KELCH repeat [structural motif]

pfam01437
Location:950 → 998

PSI; Plexin repeat.A cysteine rich repeat found in several different extracellular receptors. The function of the repeat is unknown. Three copies of the repeat are found Plexin. Two copies of the repeat are found in mahogany protein. A related C. elegans protein contains four copies of the repeat. The Met receptor contains a single copy of the repeat. The Pfam alignment shows 6 conserved cysteine residues that may form three conserved disulphide bridges, whereas shows 8 conserved cysteines. The pattern of conservation suggests that cysteines 5 and 7 (that are not absolutely conserved) form a disulphide bridge (Personal observation. A Bateman).

pfam06247
Location:2189 → 2314

Plasmod_Pvs28; Plasmodium ookinete surface protein Pvs28This family consists of several ookinete surface proteins (Pvs28) from several species of Plasmodium. Pvs25 and Pvs28 are expressed on the surface of ookinetes. These proteins are potential candidates for vaccine and induce antibodies that block the infectivity of Plasmodium vivax in immunised animals.

pfam12947
Location:1078 → 1112

EGF_3; EGF domain

pfam13415
Location:1630 → 1680

Kelch_3; Galactose oxidase, central domain

pfam13418
Location:227 → 276

Kelch_4; Galactose oxidase, central domain

cl00057
Location:1011 → 1035

vWFA; Von Willebrand factor type A (vWA) domain was originally found in the blood coagulation protein von Willebrand factor (vWF). Typically, the vWA domain is made up of approximately 200 amino acid residues folded into a classic a/b para-rossmann type of fold. The vWA domain, since its discovery, has drawn great interest because of its widespread occurrence and its involvement in a wide variety of important cellular functions. These include basal membrane formation, cell migration, cell differentiation, adhesion, haemostasis, signaling, chromosomal stability, malignant transformation and in immune defenses In integrins these domains form heterodimers while in vWF it forms multimers. There are different interaction surfaces of this domain as seen by the various molecules it complexes with. Ligand binding in most cases is mediated by the presence of a metal ion dependent adhesion site termed as the MIDAS motif that is a characteristic feature of most, if not all A domains....

BTBD29,LZTR1(22q11.21;22q11.1-q11.2), SWNTS2, NS1, NS2. Golgiverkoston vakautus.

https://www.ncbi.nlm.nih.gov/gene/8216
Leusine Zipper like transcription regulator 1 = LZTR1

Also known as

NS2; NS10; BTBD29; LZTR-1; SWNTS2

Summary

This gene encodes a member of the BTB-kelch superfamily. Initially described as a putative transcriptional regulator based on weak homology to members of the basic leucine zipper-like family, the encoded protein subsequently has been shown to localize exclusively to the Golgi network where it may help stabilize the Gogli complex. Deletion of this gene may be associated with DiGeorge syndrome. [provided by RefSeq, Jul 2008]

Expression  Ubiquitous expression in spleen (RPKM 12.6), ovary (RPKM 12.5) and 25 other tissues See more

 

Preferred Names

leucine-zipper-like transcriptional regulator 1

Names

epididymis secretory sperm binding protein
NS2, NS10, Noonan syndrome types
SWNTS2  Schwannoma

Related articles in PubMed

1. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Johnston JJ, et al. Genet Med, 2018 Oct. PMID 29469822, Free PMC Article
2. Multifocal nerve lesions and LZTR1 germline mutations in segmental schwannomatosis. Farschtschi S, et al. Ann Neurol, 2016 Oct. PMID 27472264
3. Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Smith MJ, et al. Neurology, 2015 Jan 13. PMID 25480913, Free PMC Article
4. Expanding the mutational spectrum of LZTR1 in schwannomatosis. Paganini I, et al. Eur J Hum Genet, 2015 Jul. PMID 25335493, Free PMC Article
5. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Piotrowski A, et al. Nat Genet, 2014 Feb. PMID 24362817, Free PMC Article

See all (36) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. Pathogenic mutations affecting either RIT1 or LZTR1 resulted in incomplete degradation of RIT1.
2. These clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.
3. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease.
4. LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because LZTR1 disease mutations failed to revert loss-of-function phenotypes, these findings provide a molecular rationale for LZTR1 involvement in a variety of inherited and acquired human disorders.
5. LZTR1 mutation is associated with Noonan syndrome.
6. the malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumor in SMARCB1 Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition.
7. Nerve lesions and LZTR1 germline mutations in segmental schwannomatosis.
8. Data indicate that molecular analysis of leucine-zipper-like transcription regulator 1 (LZTR1) may contribute to the molecular characterization of schwannomatosis patients.
9. We show for the first time that an inherited mutation in PBRM1 predisposes to RCC.
10. Data confirm the relationship between mutations in LZTR1 and schwannomatosis. They indicate that germline mutations in LZTR1 confer an increased risk of vestibular schwannoma.

KLHDC8A(1q32.1). S-Delta-E1

https://www.ncbi.nlm.nih.gov/protein/NP_001258792.1

Aliases for KLHDC8A Gene

• Kelch Domain Containing 8A ^{2 3 5}
• Substitute For Delta-EGFR Expression 1 ^{3 4}
• Kelch Domain-Containing Protein 8A ^{3 4}
• S-Delta-E1 ^{3 4}

KLHDC8B (3p21.31), CHL, on tärkeä genomin vakaudelle ja suojaa mitoosivirheiltä ja ,sentrosomiamplifikaatiolta

https://www.ncbi.nlm.nih.gov/gene/200942
Tämä Kelch-superperheen jäsen  suojelee mitoottisilta virheiltä, sentrosomien  amplifikaatioilta ja kromosomaaliselta  epävakaudelta (2012). Tämän KLHDC8B:n mutaatio assosioituu Hodginin lymfoomaan ja siinä tavattaviin binukleaarisiin Reed-Stenberg-soluihin.

Entrez Gene Summary for KLHDC8B Gene

• This gene encodes a protein which forms a distinct beta-propeller protein structure of kelch domains allowing for protein-protein interactions. Mutations in this gene have been associated with Hodgkin lymphoma. [provided by RefSeq, Sep 2010]
  

GeneCards Summary for KLHDC8B Gene

KLHDC8B (Kelch Domain Containing 8B) is a Protein Coding gene. Diseases associated with KLHDC8B include Lymphoma, Hodgkin, Classic and Hodgkin's Lymphoma, Nodular Sclerosis. An important paralog of this gene is KLHDC8A.

UniProtKB/Swiss-Prot Summary for KLHDC8B Gene

• Involved in pinching off the separated nuclei at the cleavage furrow and in cytokinesis (PubMed:20107318). Required for mitotic integrity and maintenance of chromosomal stability. Protects cells against mitotic errors, centrosomal amplification, micronucleus formation and aneuploidy. Plays a key role of midbody function involving abscission of the daughter cells during cytokinesis and appropriate chromosomal and nuclear segregation into the daughter cells (PubMed:22988245, PubMed:23713010).

  • KLD8B_HUMAN,Q8IXV7

Dyneiini ja kinesiini

 Kinesiini ja dyneiini

https://www.bing.com/videos/search?q=kinesin%2c+dynein&&view=detail&mid=0FAA756157B24BC7765C0FAA756157B24BC7765C&&FORM=VDRVRV

Dyneiinistä

https://www.bing.com/videos/search?q=kinesin%2c+dynein&&view=detail&mid=ECD8D5D1C4C290B80D5AECD8D5D1C4C290B80D5A&&FORM=VRDGAR

Mikrotubuluksista

What Holds a Cell Together?

https://study.com/academy/lesson/microtubules-definition-functions-structure.html

Just as our skeletons give our bodies' structure and shape, the cytoskeleton gives cells structure and shape. The cytoskeleton is responsible for lots of important cellular functions:

• It allows cells to move
• Engulf particles
• Brace themselves against pulling forces
• Transport vesicles through the cytosol
• Separate chromosomes during cell division
• Allows our muscles to contract

Clearly, things just wouldn't be the same without the cytoskeleton.
In eukaryotic cells, the cytoskeleton is made up of three major kinds of filaments: actin filaments, intermediate filaments (IF), and microtubules. Each of these filaments is a polymer, meaning that it is made up of many single subunits, like a child's building blocks snapped together to form a long chain. The subunits are called monomers, and each type of cytoskeletal filament is built out of a different kind of monomer.
The polymeric structure of cytoskeletal filaments means that they can be disassembled and rearranged at any time. This means that the cell can respond to signals in its environment and rapidly change its shape, motion, or attachment accordingly. You can imagine it like this: if the buildings in a city were made out of easily rearranged monomers, it would be easy to take them down and make new buildings in different places. We usually don't need to do this, but our cells do!
In this lesson, we'll focus on one type of cytoskeletal filament, microtubules, and learn about their structure and functions within the cell.

Microtubule Structure

Microtubules are the largest cytoskeletal filaments in cells, with a diameter of 25 nanometers. They are made out of subunits called tubulin. Each tubulin subunit is made up of one alpha and one beta tubulin that are attached to each other, so technically tubulin is a heterodimer, not a monomer. As you can see, it really does look like a tube, hence the name micro'tubule.'
In a microtubule structure, tubulin monomers are linked both at their ends and along their sides (laterally). This means that microtubules are quite stable along their lengths. Imagine that you have some plastic building blocks that are all identical and can attach to each other both at their ends and laterally. If you arranged them into a microtubule structure, and then wanted to take the structure apart, you can imagine that it would be really hard to take it apart somewhere in the middle, because how would you get the first block out? If you wanted to take it apart, you'd have to start at the ends. And indeed, this is how microtubules are assembled and disassembled, only from their ends.

Plus and Minus Ends

Since the tubulin subunits are always linked in the same direction, microtubules have two distinct ends, called the plus (+) and minus (-) ends. On the minus end, alpha tubulin is exposed, and on the plus end, beta tubulin is exposed.
Microtubules preferentially assemble and disassemble at their plus ends. An important consequence of this fact is that microtubule minus ends can be clustered together in a so-called microtubule-organizing center, or centrosome. The centrosome stays stable as the plus ends of the microtubules grow and shrink.
Microtubules are used in many important cellular functions.

KLHL25 substraattiadaptorin substraatti on ACLY, ATP: citraatti lyaasi, jonk se lähettää silppuriin.

•  http://genesdev.cshlp.org/content/30/17/1956.full.pdf 
  

  • Cullin3–KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipidsynthesis and tumor progressionCen Zhang,1,4Juan Liuet al.

  •  Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citratelyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipidsynthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3–RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation,and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes the promoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, low CUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary,our results identify CUL3–KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis anddemonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipid synthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel and critical mechanism for CUL3 in tumor suppression.[Keywords: CUL3; ACLY; KLHL25; ubiquitination; lipid synthesis; tumor

•  MINKÄLAINEN entsyymi on  ATP-sitraattilyaasi?
• 
  
• ACL; ATPCL; CLATP,    ATP- SITRAATTILYAASI- entsyymi

Summary

ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Dec 2014]

Expression

Ubiquitous expression in prostate (RPKM 37.3), kidney (RPKM 29.2) and 25 other tissues See more

Orthologs

mouse all

ACLY, ACL, ATPCL, CLATP (17q21.2) 

Sitruunahappokierron molekyylin sitraatin ATP-lyaasin merkityksestä. 

https://www.ncbi.nlm.nih.gov/gene/47 

ACL; ATPCL; CLATP

Summary

ATP citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. The enzyme is a tetramer (relative molecular weight approximately 440,000) of apparently identical subunits. It catalyzes the formation of acetyl-CoA and oxaloacetate from citrate and CoA with a concomitant hydrolysis of ATP to ADP and phosphate. The product, acetyl-CoA, serves several important biosynthetic pathways, including lipogenesis and cholesterogenesis. In nervous tissue, ATP citrate-lyase may be involved in the biosynthesis of acetylcholine. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Dec 2014]

Expression

Ubiquitous expression in prostate (RPKM 37.3), kidney (RPKM 29.2) and 25 other tissues See more

Orthologs

mouse all

https://www.ncbi.nlm.nih.gov/pubmed/29241530

1. Mendelian Randomization Study of ACLY and Cardiovascular Disease. Ference BA, et al. N Engl J Med, 2019 Mar 14. PMID 30865797
2. A role for ATP Citrate Lyase in cell cycle regulation during myeloid differentiation. Rhee J, et al. Blood Cells Mol Dis, 2019 May. PMID 30853332
3. Polarization of Human Macrophages by Interleukin-4 Does Not Require ATP-Citrate Lyase. Namgaladze D, et al. Front Immunol, 2018. PMID 30568658, Free PMC Article
4. Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes. Chen LY, et al. J Biol Chem, 2018 Aug 3. PMID 29929979, Free PMC Article
5. Binding of hydroxycitrate  ( source: Garcinia cambogia )to human ATP-citrate lyase. Hu J, et al. Acta Crystallogr D Struct Biol, 2017 Aug 1. PMID 28777081Hydroxycitrate from the fruit of Garcinia cambogia [i.e. (2S,3S)-2-hydroxycitrate] is the best-known inhibitor of ATP-citrate lyase. Well diffracting crystals showing how the inhibitor binds to human ATP-citrate lyase were grown by modifying the protein. The protein was modified by introducing cleavage sites for Tobacco etch virus protease on either side of a disordered linker. The protein crystallized consisted of residues 2-425-ENLYFQ and S-488-810 of human ATP-citrate lyase. (2S,3S)-2-Hydroxycitrate binds in the same orientation as citrate, but the citrate-binding domain (residues 248-421) adopts a different orientation with respect to the rest of the protein (residues 4-247, 490-746 and 748-809) from that previously seen. For the first time, electron density was evident for the loop that contains His760, which is phosphorylated as part of the catalytic mechanism. The pro-S carboxylate of (2S,3S)-2-hydroxycitrate is available to accept a phosphoryl group from His760. However, when co-crystals were grown with ATP and magnesium ions as well as either the inhibitor or citrate, Mg²⁺-ADP was bound and His760 was phosphorylated. The phosphoryl group was not transferred to the organic acid. This led to the interpretation that the active site is trapped in an open conformation. The strategy of designing cleavage sites to remove disordered residues could be useful in determining the crystal structures of other proteins.

See all (130) citations in PubMed

See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

What's a GeneRIF?

1. Study in human monocyte-derived macrophages suggests that ACLY may not be the major regulator of nucleocytoplasmic acetyl-CoA and IL-4-induced polarization in human macrophages.
2. regulation of ACL activity is a potentially important point of control for cell cycle regulation in the myeloid lineage.
3. Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level.
4. Increased ACLY activity in osteoarthritis chondrocytes increased nucleocytosolic acetyl-CoA, leading to increased matrix catabolism via dysregulated histone and transcription factor acetylation.
5. SLC25A1 and ACLY upregulation suggests that metabolic reprogramming in Behcet's syndrome involves the citrate pathway dysregulation.
6. ACL regulates the net amount of acetyl groups available, leading to alterations in acetylation of H3(K9/14) and H3(K27) at the MYOD locus, thus increasing MYOD expression.
7. Results show that ACLY was up-regulated in human gastric cancer (GC) tissues and cell lines and a critical downstream target of the tumor suppressor activity of miR-133b in GC.
8. ACLY and ACSS2 are both activated to produce cytosolic Ac-CoA from glucose carbon for lipogenesis during human cytomegalovirus infection.
9. ACLY facilitates histone acetylation at double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment.
10. The protein crystallized consisted of residues 2-425-ENLYFQ and S-488-810 of human ATP-citrate lyase. (2S,3S)-2-Hydroxycitrate binds in the same orientation as citrate, but the citrate-binding domain (residues 248-421) adopts a different orientation with respect to the rest of the protein (residues 4-247, 490-746 and 748-809) from that previously seen.

CENP-E (4q24), KIF10, MCPH13, PPP1R61.

https://www.ncbi.nlm.nih.gov/gene/1062

Official Symbol

CENPE

centromere protein E

Also known as

KIF10; CENP-E; MCPH13; PPP1R61

Summary

Centrosome-associated protein E (CENPE) is a kinesin-like motor protein that accumulates in the G2 phase of the cell cycle. Unlike other centrosome-associated proteins, it is not present during interphase and first appears at the centromere region of chromosomes during prometaphase. This protein is required for stable spindle microtubule capture at kinetochores which is a necessary step in chromosome alignment during prometaphase. This protein also couples chromosome position to microtubule depolymerizing activity. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Nov 2014]

Expression

Broad expression in bone marrow (RPKM 3.4), lymph node (RPKM 3.3) and 18 other tissues See more

Orthologs

 

Select item 3120138211.

BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to end-on capture of spindle microtubules.

Huang Y, Lin L, Liu X, Ye S, Yao PY, Wang W, Yang F, Gao X, Li J, Zhang Y, Zhang J, Yang Z, Liu X, Yang Z, Zang J, Teng M, Wang Z, Ruan K, Ding X, Li L, Cleveland DW, Zhang R, Yao X.

Cell Res. 2019 Jul;29(7):562-578. doi: 10.1038/s41422-019-0178-z. Epub 2019 Jun 14.

Error-free mitosis depends on accurate chromosome attachment to spindle microtubules, powered congression of those chromosomes, their segregation in anaphase, and assembly of a spindle midzone at mitotic exit. The centromere-associated kinesin motor CENP-E, whose binding partner is BubR1, has been implicated in congression of misaligned chromosomes and the transition from lateral kinetochore-microtubule association to end-on capture. Although previously proposed to be a pseudokinase, here we report the structure of the kinase domain of Drosophila melanogaster BubR1, revealing its folding into a conformation predicted to be catalytically active. BubR1 is shown to be a bona fide kinase whose phosphorylation of CENP-E switches it from a laterally attached microtubule motor to a plus-end microtubule tip tracker. Computational modeling is used to identify bubristatin as a selective BubR1 kinase antagonist that targets the αN1 helix of N-terminal extension and αC helix of the BubR1 kinase domain. Inhibition of CENP-E phosphorylation is shown to prevent proper microtubule capture at kinetochores and, surprisingly, proper assembly of the central spindle at mitotic exit. Thus, BubR1-mediated CENP-E phosphorylation produces a temporal switch that enables transition from lateral to end-on microtubule capture and organization of microtubules into stable midzone arrays.

Similar articles

 

IDE( 10q23.33) Sinkkimetalloendopeptidaasi,insuliinia hajoittava entsyymi IDE

 IDE(10q23.33)
https://www.ncbi.nlm.nih.gov/gene/3416

Official Symbol

IDEprovided by HGNC

Official Full Name

insulin degrading enzyme

Primary source

Also known as

INSULYSIN

Summary

This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.[provided by RefSeq, Sep 2009]

Expression Ubiquitous expression in skin (RPKM 17.4), testis (RPKM 9.9) and 25 other tissues See more

Preferred Names

insulin-degrading enzyme

Names

Abeta-degrading protease

insulin protease

insulinase

 Ref.

PLoS One. 2015 Jul 17;10(7):e0132455. doi: 10.1371/journal.pone.0132455. eCollection 2015. Proteasome Activity Is Affected by Fluctuations in Insulin-Degrading Enzyme Distribution.

Sbardella D¹, Tundo GR¹,^{et.el. 1}.

Abstract

Insulin-Degrading-Enzyme (IDE) is a Zn2+-dependent peptidase highly conserved throughout evolution and ubiquitously distributed in mammalian tissues wherein it displays a prevalent cytosolic localization. We have recently demonstrated a novel Heat Shock Protein-like behaviour of IDE and its association with the 26S proteasome. In the present study, we examine the mechanistic and molecular features of IDE-26S proteasome interaction in a cell experimental model, extending the investigation also to the effect of IDE on the enzymatic activities of the 26S proteasome. Further, kinetic investigations indicate that the 26S proteasome activity undergoes a functional modulation by IDE through an extra-catalytic mechanism. The IDE-26S proteasome interaction was analyzed during the Heat Shock Response and we report novel findings on IDE intracellular distribution that might be of critical relevance for cell metabolism.

2 results

1. Insulin Inhibits the Ubiquitin-Dependent Degrading ...

   https://www.researchgate.net/publication/12444208_Insulin_Inhibits_the_Ubiquitin...

   Insulin Inhibits the Ubiquitin-Dependent Degrading ...A major metabolic effect of insulin is inhibition of cellular proteolysis, but the proteolytic systems involved are unclear. Tissues have multiple proteolytic systems, including the ATP- and ubiquitin-dependent proteasome pathway. The effect of insulin on this pathway was examined in vitro and in cultured cells. Insulin inhibited ATP- and ubiquitin-dependent lysozyme degradation more than 90% by reticulocyte extract, in a dose-dependent manner (IC50 approximately 50 nM). Insulin did not reduce the conjugation of ubiquitin to lysozyme and was not itself ubiquitin-conjugated. In HepG2 cells, insulin increased ubiquitin-conjugate accumulation 80%. The association between the 26S proteasome and an intracellular protease, the insulin-degrading enzyme (IDE), was examined by a purification scheme designed to enrich for the 26S proteasome. Copurification of IDE activity and immunoreactivity with the proteasome were detected through several chromatographic steps. Glycerol gradient analysis revealed cosedimentation of IDE with the 20S proteasome and possibly with the 26S proteasome. The proteasome-associated IDE was displaced when the samples were treated with insulin. These results suggest that insulin regulates protein catabolism, at least in part, by decreasing ubiquitin-mediated proteasomal activity, and provides a new target for insulin action. The displacement of IDE from the proteasome provides a mechanism for this insulin action.
   
   ... IDE and the proteasome co-purify through a number of chromatographic steps (Duckworth et al. 1994, Bennett et al. 2000b). When IDE is either removed from the proteasome or inhibited, insulin has no influence on proteasome activity (Duckworth et al. 1994, 1998a, Hamel et al. 1998). ...
   
   Miten insulinolysiini hajoittaa insuliinia koska insuliini ei ubikitinoidu ja ole proteosomaalisesti hajoitettavissa, vaan IDE-kombinoituu proteosomaalisiin osiin ja insuliini säätelee  sen avulla proteosomaalista funktiota. 
2. Insulin-degrading enzyme (IDE): A novel heat shock-like ...
   
   https://www.researchgate.net/publication/233789522_Insulin-degrading_enzyme_IDE_A...

   Insulin-degrading enzyme (IDE) is a highly conserved zinc metallopeptidase that is ubiquitously distributed in human tissues, and particularly abundant in the brain, liver, and muscles. IDE activity has been historically associated with insulin and β-amyloid catabolism. However, over the last decade, several experimental findings have established that IDE is also involved in a wide variety of physiopathological processes, including ubiquitin clearance and Varicella Zoster Virus infection. In this study, we demonstrate that normal and malignant cells exposed to different stresses markedly up-regulate IDE in a heat shock protein (HSP)-like fashion. Additionally, we focused our attention on tumor cells and report that (i) IDE is overexpressed in vivo in tumors of the central nervous system (CNS); (ii) IDE-silencing inhibits neuroblastoma (SHSY5Y) cell proliferation and triggers cell death; (iii) IDE inhibition is accompanied by a decrease of the poly-ubiquitinated protein content and co-immunoprecipitates with proteasome and ubiquitin in SHSY5Y cells. In this work, we propose a novel role for IDE as a heat shock protein with implications in cell growth regulation and cancer progression, thus opening up an intriguing hypothesis of IDE as an anticancer target.
   
    Artikkeli vuodelta 1983: insulinolyysiksestä https://www.ncbi.nlm.nih.gov/pubmed/?term=insulinolysin

 

Keskushermostossa expressoituvat Kelch-proteiinit

Katson näistä tähän luetteloa, mutta siirrän tekstin sitten  Muisti Memory blogiin, jossa on aivoa käsittelevää asiaa.

• KLHL1, MRP2, MAYVEN related protein (13.q21.33) , Oligodendroglioille spesifinen. Excitabiliteettia edistävä.

• KLHL2, MAYVEN, Kainaattireseptorien säätely

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929045/

• KLHL16, GAN (16q23.2), Neuronien ja fibroblastien IF filamenttien  hajoitus. Gigaxoniini.  Mutaatioista seuraa axonineuropatiaproteiinia.

• KLHL17, Actinphilin, (1p36.33), Kainaattireeptorien säätely.

 https://www.ncbi.nlm.nih.gov/gene/339451#gene-expression 

• KEAP1, KLHL19.(19p13.2).
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186766/

https://www.researchgate.net/publication/221850652_Impaired_antioxydative_Keap1Nrf2_system
_and_the_downstream_stress_protein_responses_in_the_motor_neuron_of_ALS_model_mice

• KLHL37, KLHL35, ENC-1, PIG10, Tumamatrixproteiini NRP/B, Nuclear Restricted Protein, Ectodermal-Neural Cortex protein 1, CCL28, p53-induced gene 10 protein, PIG10, Tumor protein p53 inducible protein 10, TP53I10. Rajoittaa NRF2:n translaatiota ja NRF2:n kohde geenien sen kohdegeenien ilmentymistä(Epäsuorasti mutta KEAP1:stä riippumatta vastavaikuttaa Keap1/NRF2 säätelyyn kenttään siten että tumatasosta rajoittaa NRF2 vastegeenien ilmentymistä ja  mRNA NRF2:n translaatiota NRF2:ksi)