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onsdag 5 juni 2019

ZEB1 tuumoribiologiassa EMT:n mestarisäätelijä. (C2H2-tyyppinen ZNF). Cadheriinit , SWI/SNF kompleksi, CTBP 1 ja 2. SIRT1


 M.Cassandri 


 ZEB1 on C2H2- sinkkisormiproteiini ja transkriptiofaktori ja osallistuu tuumorin invaasioon ja metaboliaan. Se on EMT:n mestarisäätelijä. Sitä itseään säätelee usea signaalijärjestelmä kuten Wnt, TGF-beeta, NFkB, HIF ja miRNA:t.  Sen onkogeeninen rooli on E-cadheriini- proteiinin tukahduttaminen, onhan E-Cad  tärkein solu-solu-adheesiomolekyyli.

 ZEB1 pääsee vaikuttamaan E-Cadheriiniin tekemällä interaktion useiden kromatiinia muokkaavien  tekijäiden  kanssa, kuten CtBP ja Swi/SNF-kompleksi.

 Toisaalta ZEB1 aktivoi suoraan niiden geenien promoottoreita, jotka osallistuvat EMT-ohjelmaan. ZEB1 tekee interaktion joko SMAD- proteiinien tai p300/CAF kanssa ja aktivoi TGFbeetan kohdegeenin CDH2 (N-Cadheriinin, joka on mesenkymaalinen  neuronaalinen  cadheriini ja olennainen tuumorin progressiolle).

ZEB1- yli-ilmenemä useissa syöpälinjoissa ( havaittu haima-, keuhko-, maksasyövässä, osteosarkoomassa, rintasyövässä, paksusuolisyövässä) indusoi EMT:tä ja edistää solujen invaasiota. Tieto vuodelta 2017) .

ZEB1  (10p11.22) https://www.ncbi.nlm.nih.gov/gene/6935
BZP; TCF8; AREB6; FECD6; NIL2A; PPCD3; ZFHEP; ZFHX1A; DELTAEF1. This gene encodes a zinc finger transcription factor. The encoded protein likely plays a role in transcriptional repression of interleukin 2. Mutations in this gene have been associated with posterior polymorphous corneal dystrophy-3 and late-onset Fuchs endothelial corneal dystrophy. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Mar 2010]
Preferred Names:
 zinc finger E-box-binding homeobox 1,
Names:
 delta-crystallin enhancer binding factor 1,
negative regulator of IL2,
posterior polymorphous corneal dystrophy 3,
transcription factor 8 (represses interleukin 2 expression.


Tästä ZEB1-geenistä on erikseen  toinen otsikko ja lisäartikkeleista  maininta.
Tässä kirjoitan  artikkelin mainitsemista tekijöistä, joita on EMT prosessissa.

EMT = Epithelial Mesenchymal Transition

E-Cadherin , https://www.ncbi.nlm.nih.gov/gene/999
CDH1, cadherin 1,  (16q22) Calcium dependent  adhesion protein (epithelial), Cell-CAM 120/80. uvomodulin.
Preferred Names: cadherin-1
Names:
CAM 120/80
E-cadherin 1
cadherin 1, E-cadherin (epithelial)
cadherin 1, type 1, E-cadherin (epithelial)
calcium-dependent adhesion protein, epithelial
cell-CAM 120/80
epididymis secretory sperm binding protein
epithelial cadherin
uvomorulin

N-Cadherin,https://www.ncbi.nlm.nih.gov/gene/1000
CDH2. cadherin 2, (18q12.1), Calcium dependent adhesion protein (neuronal).
Preferred Names, cadherin-2
Names: N-cadherin 1
cadherin 2, type 1, N-cadherin (neuronal)
calcium-dependent adhesion protein, neuronal
neural cadherin


Näistä on  joitakin omia otsikoita tässä blogissakin:  Olen katsonut netistä signaaliteiden kuvauksia  opetusvideoista.
Wnt
TGF-beta
SMAD
NF-kB
HIF
miRNA

CtBP

CTBP1,(4p16.3)  C-terminal binding protein 1, brefeldin. https://www.ncbi.nlm.nih.gov/gene/1487
 BARS; HADDTS
This gene encodes a protein that binds to the C-terminus of adenovirus E1A proteins. This phosphoprotein is a transcriptional repressor and may play a role during cellular proliferation. This protein and the product of a second closely related gene, CTBP2, can dimerize. Both proteins can also interact with a polycomb group protein complex which participates in regulation of gene expression during development. Alternative splicing of transcripts from this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008] Expression  Ubiquitous expression in spleen (RPKM 9.3), prostate (RPKM 7.1) and 25 other tissues See more
Preferred Names:C-terminal-binding protein 1
Names: brefeldin A-ribosylated substrate

CTBP2, (10q26.13), C-terminal binding protein 2 , ribeye ; 2 isoforms.  https://www.ncbi.nlm.nih.gov/gene/1488  This gene produces alternative transcripts encoding two distinct proteins. One protein is a transcriptional repressor, while the other isoform is a major component of specialized synapses known as synaptic ribbons. Both proteins contain a NAD+ binding domain similar to NAD+-dependent 2-hydroxyacid dehydrogenases. A portion of the 3' untranslated region was used to map this gene to chromosome 21q21.3; however, it was noted that similar loci elsewhere in the genome are likely. Blast analysis shows that this gene is present on chromosome 10. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Feb 2014] Expression  Ubiquitous expression in thyroid (RPKM 13.6), endometrium (RPKM 9.4) and 24 other tissues See more
 Preferred Names: C-terminal-binding protein 2
Names: ribeye Transcript Variant: This variant (2) represents the longest transcript and encodes the longer isoform (2). This protein localizes to synaptic ribbons, synapses used for fast tonic neurotransmitter release in a subset of specialized neurons.
´
Swi/SNF complexhttps://www.ncbi.nlm.nih.gov/pubmed/28262751

Genes encoding subunits of SWI/SNF (BAF) chromatin remodelling complexes are collectively altered in over 20% of human malignancies, but the mechanisms by which these complexes alter chromatin to modulate transcription and cell fate are poorly understood. Utilizing mouse embryonic fibroblast and cancer cell line models, here we show via ChIP-seq and biochemical assays that SWI/SNF complexes are preferentially targeted to distal lineage specific enhancers and interact with p300 to modulate histone H3 lysine 27 acetylation. We identify a greater requirement for SWI/SNF at typical enhancers than at most super-enhancers and at enhancers in untranscribed regions than in transcribed regions. Our data further demonstrate that SWI/SNF-dependent distal enhancers are essential for controlling expression of genes linked to developmental processes. Our findings thus establish SWI/SNF complexes as regulators of the enhancer landscape and provide insight into the roles of SWI/SNF in cellular fate control.

ZEB1- SIRT feedback 
https://www.ncbi.nlm.nih.gov/pubmed/30304565

2019 Mar;120(3):3727-3735. doi: 10.1002/jcb.27653. Epub 2018 Oct 10.SIRT1-ZEB1-positive feedback promotes epithelial-mesenchymal transition process and metastasis of  Abstract. Osteosarcoma is the most common malignant bone cancer that mainly affects children and young adults. Recently, the NAD+ -dependent deacetylase, sirtuin 1 (SIRT1), has been reported to play a key role in the development of malignant tumors. The study aimed to investigate the role of SIRT1 in osteosarcoma and explore its underlying oncogenic mechanisms. The prognostic value of SIRT1 in osteosarcoma was assessed through detection of SIRT1 expression based on osteosarcoma biopsy tissue. Then, to further investigate the effect of SIRT1 in osteosarcoma, osteosarcoma cells were treated with small interfering RNA SIRT1 and overexpressed SIRT1 to detect the cell migration, invasion, and epithelial-mesenchymal transition (EMT). The levels of SIRT1 expression were significantly higher in osteosarcoma tissues than those in adjacent normal tissues, and the SIRT1 protein level may be coupled with metastatic and poor prognosis risk in patients with osteosarcoma. Moreover, SIRT1 silencing inhibited the migration as well as invasion ability of osteosarcoma cells in vitro, and SIRT1 upregulation reversed those effects. Finally, we found that SIRT1-ZEB1-positive feedback enhanced the EMT process and metastasis of osteosarcoma. Altogether, the results of the current study revealed that high levels of SIRT1 might be a biomarker for a high metastatic rate in patients with osteosarcoma, which suggested that inhibition of SIRT1 might be promising for the therapeutics of osteosarcoma.

KEYWORDS:

SIRT1; ZEB1; epithelial-mesenchymal transition; metastasis; osteosarcoma

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