p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance
- 8 September 2014
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 34 (27), 3568-3581
- https://doi.org/10.1038/onc.2014.287
Abstract
The DNA damage response (DDR) helps to maintain genome integrity, suppress tumorigenesis and mediate the radiotherapeutic and chemotherapeutic effects on cancer. Here we report that p57Kip2, a cyclin-dependent kinase (CDK) inhibitor implicated in the development of tumor-prone Beckwith–Wiedemann syndrome, is an effector molecule of the DNA-damage response. Genotoxic stress induces p57Kip2 expression via the bone morphogenetic protein-Smad1 and Atm-p38MAPK-Atf2 pathways in p53-proficient or -deficient cells and requires the Smad1-Atf2 complex that facilitates their recruitment to the p57Kip2 promoter. Elevated p57Kip2 induces G1/S phase cell cycle arrest but inhibits cell death in response to DNA damage and acts in parallel with p53 to suppress cell transformation and tumor formation. p57Kip2 is also upregulated in stage I and II clinical rectal tumor samples, likely due to genome instability of precancerous and/or early cancer cells. Targeting p57Kip2 in primary rectal cancer cells and tumor models resulted in increased sensitivity to doxorubicin, suggesting that p57Kip2 has a role in chemoresistance, which is consistent with its pro-survival function. These findings place p57Kip2 in DDR and uncover molecular mechanisms by which p57Kip2 suppresses tumorigenesis and causes chemoresistance.Keywords
This publication has 63 references indexed in Scilit:
- Identification of 5-Iodotubercidin as a Genotoxic Drug with Anti-Cancer PotentialPLOS ONE, 2013
- p57KIP2 control of actin cytoskeleton dynamics is responsible for its mitochondrial pro-apoptotic effectCell Death & Disease, 2012
- Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitorsTrends in Cell Biology, 2012
- DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by MK2-Mediated RNA StabilizationMolecular Cell, 2010
- The DNA Damage Response: Making It Safe to Play with KnivesMolecular Cell, 2010
- S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage responseThe EMBO Journal, 2010
- Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2Current Opinion in Cell Biology, 2009
- BMP2 and BMP6 control p57Kip2 expression and cell growth arrest/terminal differentiation in normal primary human epidermal keratinocytesCellular Signalling, 2007
- p53-Deficient Cells Rely on ATM- and ATR-Mediated Checkpoint Signaling through the p38MAPK/MK2 Pathway for Survival after DNA DamageCancer Cell, 2007
- New insights into TGF-β–Smad signallingTrends in Biochemical Sciences, 2004