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p 16 Ink 4 a Tumor Suppressor Function in Lung Cancer Cells Involves Cyclin-dependent Kinase 2 Inhibition by Cip / Kip Protein Redistribution 1
| Content Provider | Semantic Scholar |
|---|---|
| Author | Grimison, Bryn Langan, Thomas A. Sclafani, Robert A. |
| Copyright Year | 2000 |
| Abstract | As cell cycle regulators whose activity is frequently altered in human cancers, cyclin-dependent kinases (cdks) are novel targets for therapeutic intervention. cdk inhibition is an emerging strategy for the treatment of non-small cell lung carcinomas (NSCLCs) because most derived cell lines express functional retinoblastoma protein (Rb) but appear to bypass its function with inappropriate cdk activity. Elevated cdk4/ cdk6 activity in NSCLC cells is often due to inactivation of the p16 cdk inhibitor. To model the effects of cdk4/cdk6 inhibition, we have expressed p16 in a Rb-positive NSCLC cell line that lacks endogenous p16 expression. Whereas cdk4/cdk6 inhibition and Rb dephosphorylation are expected on p16 expression, we have also observed indirect cdk2 inhibition. cdk2 inactivation by the redistribution of other cdk inhibitors may be required for p16mediated growth suppression of Rb-positive cells. The implications of such a requirement on the use of chemical cdk inhibitors to treat human cancers will be discussed. Introduction cdk activity is essential for eukaryotic cell proliferation and, when deregulated, can contribute to oncogenic transformation (1–3). Consisting of a catalytic subunit (cdk1 to cdk8) and a regulatory subunit (cyclin A to cyclin H), specific cyclincdk complexes are believed to promote cell cycle progression at discrete “execution points” of the cell cycle. cdk activation is regulated at multiple levels, including: (a) transient synthesis and degradation of regulatory subunits; (b) cyclin-cdk complex assembly; (c) subunit phosphorylation and dephosphorylation; (d) subcellular localization; and (e) binding of various protein inhibitors (4). Because cells that commit to chromosome duplication in S phase will generally complete a cell cycle, proliferative decisions are made in G1 phase, when cdk activity is determined by a balance of growth-stimulatory and growth-inhibitory signals. Above a critical threshold, G1-phase cdk activity promotes Rb phosphorylation and G1-S-phase transition. cdk activity in transformed cells is often uncoupled from regulatory signals, allowing Rb phosphorylation and cell proliferation despite serum deprivation, cell-cell contact, loss of anchorage, and the presence of inhibitory cytokines. Rb regulation of the G1-S-phase transition is frequently targeted for inactivation in human cancers (reviewed in Ref. 5). Whereas the Rb-1 gene is frequently deleted or mutated during the development of small cell lung cancers (6), most NSCLC cells express functional Rb but show altered regulation of cdk4 and the closely related enzyme, cdk6 (7–9). Common mutational events in NSCLC that are thought to contribute to unregulated cdk activity include K-ras activation, D-type cyclin overexpression, and inactivation of p16, whose expression is lost in approximately one-third of NSCLC tumors and in the majority of NSCLC-derived cell lines (7–11). Additionally, point mutations in either p16 or cdk4 which prevent their association appear to compromise cdk4 inhibition and Rb function in other human cancers |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cgd.aacrjournals.org/cgi/reprint/11/10/507.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
