ArticleCell cycle (Georgetown, Tex.)2013
CDK inhibitor p57 (Kip2) is downregulated by Akt during HER2-mediated tumorigenicity.
Article in Cell cycle (Georgetown, Tex.), 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 38 citations in OpenAlex.
- p57International journal of molecular sciences · 2024Article
- Genetic insights into the mechanisms of proliferative glomerulonephritis.The Journal of clinical investigation · 2024Article
- CIP/KIP and INK4 families as hostages of oncogenic signaling.Cell division · 2024Review
- EGF Relays Signals to COP1 and Facilitates FOXO4 Degradation to Promote Tumorigenesis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2020Article
- Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors.International journal of molecular sciences · 2020Review
- CSN6-TRIM21 axis instigates cancer stemness during tumorigenesis.British journal of cancer · 2020Article
- Screening ginseng saponins in progenitor cells identifies 20(R)-ginsenoside RhScientific reports · 2020Article
- Article
- Evolutionary Approach of Intrinsically Disordered CIP/KIP Proteins.Scientific reports · 2019Article
- The KIP/CIP family members p21^{Waf1/Cip1} and p57^{Kip2} as diagnostic markers for breast cancer.Cancer biomarkers : section A of Disease markers · 2017Article
- Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma.Nature medicine · 2015Article
- The role of cytoplasmic p57 in invasion of hepatocellular carcinoma.BMC gastroenterology · 2015Article
- ERK2-Dependent Phosphorylation of CSN6 Is Critical in Colorectal Cancer Development.Cancer cell · 2015Article
- p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance.Oncogene · 2015Article
- Article
- CSN6 positively regulates c-Jun in a MEKK1-dependent manner.Cell cycle (Georgetown, Tex.) · 2015Article
- Cellular Response upon Stress: p57 Contribution to the Final Outcome.Mediators of inflammation · 2015Review
- Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase.Cell division · 2015Article
- TAp63gamma is required for the late stages of myogenesis.Cell cycle (Georgetown, Tex.) · 2015Article
- Akt destabilizes p57 (Kip2) : Akt at the converging crossroad?Cell cycle (Georgetown, Tex.) · 2013Article
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9 authors at 2 institutions in 2 countries.
Funding
Abstract
HER2/neu oncogene is frequently deregulated in cancers, and the (PI3K)-Akt signaling is one of the major pathways in mediating HER2/neu oncogenic signal. p57 (Kip2) , an inhibitor of cyclin-depependent kinases, is pivotal in regulating cell cycle progression, but its upstream regulators remain unclear. Here we show that the HER2-Akt axis is linked to p57 (Kip2) regulation, and that Akt is a negative regulator of p57 (Kip2) . Ectopic expression of Akt can decrease the expression of p57 (Kip2) , while Akt inhibition leads to p57 (Kip2) stabilization. Mechanistic studies show that Akt interacts with p57 (Kip2) and causes cytoplasmic localization of p57 (Kip2) . Akt phosphorylates p57 on Ser 282 or Thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination. Importantly, the negative impact of HER2/Akt on p57 stability contributes to HER2-mediated cell proliferation, transformational activity and tumorigenicity. p57 restoration can attenuate these defects caused by HER2. Significantly, Kaplan-Meier analysis of tumor samples demonstrate that in tumors where HER2 expression was observed, high expression levels of p57 (Kip2) were associated with better overall survival. These data suggest that HER2/Akt is an important negative regulator of p57 (Kip2) , and that p57 restoration in HER2-overexpressing cells can reduce breast tumor growth. Our findings indicate the applicability of employing p57 regulation as a therapeutic intervention in HER2-overexpressing cancers.
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