| Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A. | |
| | |
MedLine Citation:
|
PMID: 20228808 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The dual specificity (Tyr/Thr) phosphatase Cdc25A activates cyclin-dependent kinases (Cdks) to promote cell-cycle progression and has significant oncogenic potential. Cdc25A protein levels are regulated tightly in normal tissues, but many human cancers overexpress Cdc25A. The underlying mechanism for overexpression has been enigmatic. Here we show that Cdc25A is stabilized by the ubiquitin hydrolase Dub3. Upon binding Cdc25A, Dub3 removes the polyubiquitin modifications that mark Cdc25A for proteasomal degradation. Dub3 knockdown in cells increased Cdc25A ubiquitylation and degradation, resulting in reduced Cdk/Cyclin activity and arrest at G1/S and G2/M phases of the cell cycle. In contrast, acute Dub3 overexpression produced a signature response to oncogene induction: cells accumulated in S and G2 because of replication stress, and activated a DNA damage response. Dub3 also transformed NIH-3T3 cells and cooperated with activated H-Ras to promote growth in soft agar. Importantly, we show that Dub3 overexpression is responsible for an abnormally high level of Cdc25A in a subset of human breast cancers. Moreover, Dub3 knockdown significantly retarded the growth of breast tumour xenografts in nude mice. As a major regulator of Cdc25A, Dub3 is an example of a transforming ubiquitin hydrolase that subverts a key component of the cell cycle machinery. |
| | |
Authors:
|
Yaron Pereg; Bob Y Liu; Karen M O'Rourke; Meredith Sagolla; Anwesha Dey; Laszlo Komuves; Dorothy M French; Vishva M Dixit |
Related Documents
:
|
17363508 - Inactivation of glycogen synthase kinase-3beta, a downstream target of the raf-1 pathwa... 16755028 - The inhibitory effect of aryl hydrocarbon receptor repressor (ahrr) on the growth of hu... 11123298 - The identification of a novel t cell activation state controlled by a diabetogenic gene. 17072338 - Rack1 inhibits colonic cell growth by regulating src activity at cell cycle checkpoints. 7319948 - Intake, digestibility, ruminal characteristics and rate of passage of orchardgrass diet... 21315488 - Down-regulation of cyclin d1 by small interfering rna inhibits cell growth and induces ... |
Publication Detail:
|
Type: Journal Article Date: 2010-03-14 |
Journal Detail:
|
Title: Nature cell biology Volume: 12 ISSN: 1476-4679 ISO Abbreviation: Nat. Cell Biol. Publication Date: 2010 Apr |
Date Detail:
|
Created Date: 2010-04-02 Completed Date: 2010-04-26 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 100890575 Medline TA: Nat Cell Biol Country: England |
Other Details:
|
Languages: eng Pagination: 400-6 Citation Subset: IM |
Affiliation:
|
Department of Physiological Chemistry, 1 DNA Way, South San Francisco, California, 94080, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Apoptosis Breast Neoplasms / genetics, metabolism*, pathology Cell Cycle Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic / genetics, metabolism* DNA Damage Endopeptidases / genetics, metabolism* Enzyme Stability Female Gene Expression Regulation, Neoplastic Genes, myc Genes, ras Humans Mice Mice, Nude NIH 3T3 Cells Oncogenes* Proteasome Endopeptidase Complex / metabolism Protein Processing, Post-Translational* RNA Interference Time Factors Transfection Transplantation, Heterologous Tumor Burden Ubiquitination cdc25 Phosphatases / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
|
EC 3.1.3.48/CDC25A protein, human; EC 3.1.3.48/cdc25 Phosphatases; EC 3.4.-/DUB-3 protein, human; EC 3.4.-/Endopeptidases; EC 3.4.25.1/Proteasome Endopeptidase Complex |
| Comments/Corrections | |
Comment In:
|
Nat Cell Biol. 2010 Apr;12(4):311-3
[PMID:
20228807
]
|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Cdc25A and Dub3 in a high-stakes balancing act.
Next Document: BRD7 is a candidate tumour suppressor gene required for p53 function.