The function of p27^KIP1during tumor development

Abstract

Abbreviations: CDKs, cycle dependent kinases; CKIs, cyclin dependent kinase inhibitors; CRM1, chromosome region maintenance 1 protein; Pin1, peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; RSK1, ribosomal S6 kinase 1; SCF, skp1-cullin1-F-box protein; Skp2, S-phase kinase-associated protein 2 AbstractTimely cell cycle regulation is conducted by sequential activation of a family of serine-threonine kinases called cycle dependent kinases (CDKs). Tight CDK regulation involves cyclin dependent kinase inhibitors (CKIs) which ensure the correct timing of CDK activation in different phases of the cell cycle. One CKI of importance is p27 KIP1. The regulation and cellular localization of p27 KIP1 can result in biologically contradicting roles when found in the nucleus or cytoplasm of both normal and tumor cells. The p27 KIP1 protein is mainly regulated by proteasomal degradation and its downregulation is often correlated with poor prognosis in several types of human cancers. The protein can also be functionally inactivated by cytoplasmic localization or by phosphorylation. The p27 KIP1 protein is an unconventional tumor suppressor because mutation of its gene is extremely rare in tumors, implying the normal function of the protein is deranged during tumor development. While the tumor suppressor function is mediated by p27 KIP1 's inhibitory interactions with the cyclin/CDK complexes, its oncogenic function is cyclin/CDK independent, and in many cases correlates with cytoplasmic localization. Here we review the basic features and novel aspects of the p27 KIP1 protein, which displays genetically separable tumor suppressing and oncogenic functions.

Silencing of ECHDC1 inhibits growth of gemcitabine‑resistant bladder cancer cells

“…The p27 protein is a member of the Cip/Kip family of cyclin-dependent kinase inhibitors that bind to cyclin/CDK complexes and inhibit their activities. p27 arrests the cell cycle in the G1 phase (22)(23)(24). In agreement with these reports, we observed increased p27 expression and G1 arrest in bladder cancer cells in which ECHDC1 was silenced.…”

Cell Cycle Regulatory Proteins in Breast Cancer: Molecular Determinants of Drug Resistance and Targets for Anticancer Therapies

“…In cyclin A, p27 binds within a groove formed by conserved cyclin box residues while to CDK2, it mimics ATP and inserts into the catalytic cleft (Russo et al, 1996). Similar to p21, tumor promoting activities have been reported for p27 as well (Besson et al, 2007;Blagosklonny, 2002;Lee & Kim, 2009). Despite the dual nature of p27, as a tumor suppressor and tumor promoter, its ability to inhibit CDK complexes is still considered very important Moreover, in a meta-analysis, reduced p27 has been recognized as an independent prognostic factor for poor overall and disease-free survival breast cancer patients (Guan et al, 2010), suggesting that agents that could activate p27 would have clinical utility.…”

Early Detection of Oral Squamous Cell Carcinoma ( O SCC ) – Role of Genetics: A Literature Review

“…It associates with several CDK complexes, resulting in loss of their activity and inability in phosphorylating the retinoblastoma (Rb) gene. Although it rarely gets mutated, reduced levels of p27 protein expression have been reported in various human tumours, including OSCC [29].…”