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torsdag 24 oktober 2019

KLHL20(1q25.1) , KLEIP, KLHLX. Säätää ylös HIF2a. Neurotroofinen vaikutus.

https://www.ncbi.nlm.nih.gov/gene/27252
Also known as KHLHX; KLEIP; KLHLX
Summary The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 44-56 amino acid repeat motif. The kelch motif appears in many different polypeptide contexts and contains multiple potential protein-protein contact sites. Members of this family are present both throughout the cell and extracellularly, with diverse activities. [provided by RefSeq, Jul 2008]
Expression Ubiquitous expression in testis (RPKM 10.0), fat (RPKM 7.7) and 25 other tissues See more
Preferred Names
kelch-like protein 20
Names
Kelch motif containing protein
kelch-like ECT2-interacting protein (KLEIP)
kelch-like protein X
  1. The BTB-Kelch protein KLEIP controls endothelial migration and sprouting angiogenesis. Nacak TG, et al. Circ Res, 2007 Apr 27. PMID 17395875
  2. Kelch-like 20 up-regulates the expression of hypoxia-inducible factor-2α through hypoxia- and von Hippel-Lindau tumor suppressor protein-independent regulatory mechanisms. Higashimura Y, et al. Biochem Biophys Res Commun, 2011 Sep 23. PMID 21888897 AbstractDespite their structural similarity, hypoxia-inducible factor (HIF)-1α and HIF-2α have distinct functional properties and exhibit distinct spatiotemporal expression patterns, suggesting that the expressions of the two proteins are regulated by different mechanisms. To clarify the HIF-2α-specific regulatory mechanism, we screened HIF-2α-associated proteins in a yeast two-hybrid system and identified kelch-like 20 (KLHL20). HIF-2α, but not HIF-1α, interacted with KLHL20. siRNA-mediated knockdown of KLHL20 decreased HIF-2α protein, but not HIF-2α mRNA or HIF-1α protein. Depletion of KLHL20 decreased hypoxia-induced HIF activity, and consequently resulted in decreased expression levels of HIF-2α-responsive genes such as VEGF and CITED2. In contrast, overexpression of KLHL20 increased the expression levels and transcriptional activities of the O(2)-sensitive wild-type and O(2)-insensitive mutant forms of HIF-2α. KLHL20 siRNA also inhibited HIF-2 activity in von Hippel-Lindau tumor suppressor protein (pVHL)-deficient 786-O cells. These results indicate that KLHL20 is a novel player that regulates HIF-2α protein expression through mechanisms independent of hypoxia and pVHL.
HIF-2A : Notch, Wnt, stemness:https://www.ncbi.nlm.nih.gov/pubmed/30340507/
  1. Novel kelch-like protein, KLEIP, is involved in actin assembly at cell-cell contact sites of Madin-Darby canine kidney cells. Hara T, et al. Mol Biol Cell, 2004 Mar. PMID 14668487, Free PMC Article
  2. PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth. Lin MY, et al. J Cell Biol, 2011 Jun 13. PMID 21670212, Free PMC Article
  3. KLHL39 suppresses colon cancer metastasis by blocking KLHL20-mediated PML and DAPK ubiquitination. Chen HY, et al. Oncogene, 2015 Oct 1. PMID 25619834
See all (32) citations in PubMed

Lisälinkkejä: 

https://www.ncbi.nlm.nih.gov/pubmed/29910671

2018 Apr 3;15(7):674-681. doi: 10.7150/ijms.23782. eCollection 2018.
Inhibition of CRL-NEDD8 pathway as a new approach to enhance ATRA-induced differentiation of acute promyelocytic leukemia cells.
Liu S1, Wan J1, Kong Y1, Zhang Y1, Wan L1, Zhang Z1.1
Department of Clinical laboratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.
Abstract
The cullin-RING ligase (CRL)-NEDD8 pathway maintains essential cellular processes, including cell cycle progression, apoptosis, autophagy, DNA repair, antigen processing and signal transduction. Growing evidence demonstrates that the alteration of the CRL-NEDD8 pathway in some cancers constitutes an attractive target for therapeutic intervention, but the roles of CRL-NEDD8 pathway in acute promyelocytic leukemia (APL) is still unclear. In the present study, we found that ATRA could decrease the expression of NEDD8-activating enzyme E1 (NAE1) and inhibit the neddylation of cullin1 and cullin3 in the APL cell line NB4.

 Inactivation of cullin neddylation promoted self-degradation of F-box proteins (Skp2, KLHL20, βTrCP) and up-regulated the protein expression of p27kip, DEPTOR and DAPK1. MLN4924, a novel inhibitor of NAE1, significantly suppressed cell growth and enhanced apoptosis of APL cells by blocking cullin neddylation and subsequent accumulation of CRL E3 substrates. Furthermore, MLN4924 effectively enhanced ATRA-induced differentiation of APL cells by promoting autophagy. Our findings not only provide further insights into the mechanism of the CRL-NEDD8 axis, but also provide a better understanding of this pathway as a potential target for therapeutic intervention in APL.
KEYWORDS:
ATRA; CRL-NEDD8; MLN4924; differentiation; neddylation
DOI:
10.7150/ijms.23782
[Indexed for MEDLINE]
Free PMC Article

LINKS:
 https://www.ncbi.nlm.nih.gov/pubmed/31629725
2019 Oct 14. pii: S1658-3876(19)30076-7. doi: 10.1016/j.hemonc.2019.08.006. [Epub ahead of print]
Outcomes of high-risk acute promyelocytic leukemia patients treated with arsenic trioxide (ATO)/all trans retinoic acid (ATRA) based induction and consolidation without maintenance phase: A case Series.
Shah G1, Mikhail FM2, Bachiasvili K3, Vachhani P3, Erba HP4, Papadantonakis N5.
Author information
1


2019 Oct 14. pii: S1658-3876(19)30076-7. doi: 10.1016/j.hemonc.2019.08.006. [Epub ahead of print]
Outcomes of high-risk acute promyelocytic leukemia patients treated with arsenic trioxide (ATO)/all trans retinoic acid (ATRA) based induction and consolidation without maintenance phase: A case Series.
Shah G1, Mikhail FM2, Bachiasvili K3, Vachhani P3, Erba HP4, Papadantonakis N5.
Author information
1
Department of Internal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Upplagd av kl.
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