| Tandem E2F binding sites in the promoter of the p107 cell cycle regulator control p107 expression and its cellular functions. | |
| | |
MedLine Citation:
|
PMID: 20585628 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The retinoblastoma tumor suppressor (Rb) is a potent and ubiquitously expressed cell cycle regulator, but patients with a germline Rb mutation develop a very specific tumor spectrum. This surprising observation raises the possibility that mechanisms that compensate for loss of Rb function are present or activated in many cell types. In particular, p107, a protein related to Rb, has been shown to functionally overlap for loss of Rb in several cellular contexts. To investigate the mechanisms underlying this functional redundancy between Rb and p107 in vivo, we used gene targeting in embryonic stem cells to engineer point mutations in two consensus E2F binding sites in the endogenous p107 promoter. Analysis of normal and mutant cells by gene expression and chromatin immunoprecipitation assays showed that members of the Rb and E2F families directly bound these two sites. Furthermore, we found that these two E2F sites controlled both the repression of p107 in quiescent cells and also its activation in cycling cells, as well as in Rb mutant cells. Cell cycle assays further indicated that activation of p107 transcription during S phase through the two E2F binding sites was critical for controlled cell cycle progression, uncovering a specific role for p107 to slow proliferation in mammalian cells. Direct transcriptional repression of p107 by Rb and E2F family members provides a molecular mechanism for a critical negative feedback loop during cell cycle progression and tumorigenesis. These experiments also suggest novel therapeutic strategies to increase the p107 levels in tumor cells. |
| | |
Authors:
|
Deborah L Burkhart; Stacey E Wirt; Anne-Flore Zmoos; Michael S Kareta; Julien Sage |
Related Documents
:
|
3515058 - Magnesium and cell cycle control: an update. 17072888 - Dna replication in the fission yeast: robustness in the face of uncertainty. 10950718 - Cell cycle. replication meets cohesion. . 21445578 - Synergetic effects of dna demethylation and histone deacetylase inhibition in primary r... 17888458 - S-adenosyl-l-methionine counteracts mitotic disturbances and cytostatic effects induced... 8612518 - Short photoperiod-dependent down-regulation of thyrotropin-alpha and -beta in hamster p... |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-06-24 |
Journal Detail:
|
Title: PLoS genetics Volume: 6 ISSN: 1553-7404 ISO Abbreviation: PLoS Genet. Publication Date: 2010 Jun |
Date Detail:
|
Created Date: 2010-06-29 Completed Date: 2010-09-27 Revised Date: 2011-03-11 |
Medline Journal Info:
|
Nlm Unique ID: 101239074 Medline TA: PLoS Genet Country: United States |
Other Details:
|
Languages: eng Pagination: e1001003 Citation Subset: IM |
Affiliation:
|
Departments of Pediatrics and Genetics, Stanford Medical School, Stanford, California, United States of America. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Base Sequence Binding Sites Cell Cycle* Cell Cycle Proteins Cells, Cultured Conserved Sequence E2F Transcription Factors / metabolism* Humans Mice Molecular Sequence Data Promoter Regions, Genetic* Retinoblastoma-Like Protein p107 / chemistry, genetics, metabolism* Sequence Alignment Transcription, Genetic |
| Chemical | |
Reg. No./Substance:
|
0/Cell Cycle Proteins; 0/E2F Transcription Factors; 0/Rbl1 protein, mouse; 0/Retinoblastoma-Like Protein p107 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Web-based, participant-driven studies yield novel genetic associations for common traits.
Next Document: A viral microRNA down-regulates multiple cell cycle genes through mRNA 5'UTRs.