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Published on: May 14, 2016
p205, a potential tumor suppressor, inhibits cell proliferation via multiple pathways of cell cycle regulation
Benyam Asefa1, Jonathan M Dermott, Philipp Kaldis
1Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute-Frederick, Building 560, Room 31-56, Frederick, MD 21702-1201, USA.
Abstract:
p205 is a member of the interferon-inducible p200 family of proteins that regulate cell proliferation. Over-expression of p205 inhibits cell growth, although its mechanism of action is currently unknown. Therefore, we evaluated the effect of p205 on the p53 and Rb-dependent pathways of cell cycle regulation. p205 expression results in elevated levels of p21, and activates the p21 promoter in vitro in a p53-dependent manner. In addition, p205 induces increased expression of Rb, and binds directly to Rb and p53. Interestingly, p205 also induces growth inhibition independent of p53 and Rb by delaying G2/M progression in proliferating cells, and is a substrate for Cdk2 kinase activity. Finally, we have identified other binding partners of p205 by a yeast two-hybrid screen, including the paired homeodomain protein HoxB2. Taken together, our results indicate that p205 induces growth arrest by interaction with multiple transcription factors that regulate the cell cycle, including but not entirely dependent on the Rb- and p53-mediated pathways of growth inhibition.
Insights
p205 protein inhibits cell growth by interacting with cell cycle regulators like p53 and Rb. It also independently delays cell cycle progression, revealing a complex mechanism for cell growth arrest.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- p205 is an interferon-inducible protein belonging to the p200 family.
- p205 regulates cell proliferation, with overexpression inhibiting cell growth.
- The precise mechanism of p205-mediated growth inhibition is not fully understood.
Purpose of the Study:
- To investigate the effect of p205 on p53 and Rb-dependent cell cycle regulation pathways.
- To elucidate the molecular mechanisms underlying p205-induced growth inhibition.
Main Methods:
- Assessed p205 expression and its impact on cell cycle regulators.
- Performed in vitro p21 promoter activation assays.
- Utilized yeast two-hybrid screening to identify binding partners.
- Investigated p205 interaction with p53, Rb, and Cdk2 kinase activity.
Main Results:
- p205 expression elevates p21 levels and activates the p21 promoter in a p53-dependent manner.
- p205 increases Rb expression and directly binds to both Rb and p53.
- p205 induces p53/Rb-independent growth inhibition by delaying G2/M phase progression.
- p205 is a substrate for Cdk2 kinase and interacts with HoxB2.
Conclusions:
- p205 induces cell growth arrest through interactions with multiple cell cycle regulatory factors.
- The growth inhibitory effects of p205 involve both p53/Rb-dependent and independent pathways.
- p205 represents a novel target for understanding and potentially manipulating cell cycle control.
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