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Growth suppression by p16ink4 requires functional retinoblastoma protein
R H Medema1, R E Herrera, F Lam
1Whitehead Institute for Biomedical Research, Nine Cambridge Center, MA 02142, USA.
Abstract:
p16ink4 has been implicated as a tumor suppressor that is lost from a variety of human tumors and human cell lines. p16ink4 specifically binds and inhibits the cyclin-dependent kinases 4 and 6. In vitro, these kinases can phosphorylate the product of the retinoblastoma tumor suppressor gene. Thus, p16ink4 could exert its function as tumor suppressor through inhibition of phosphorylation and functional inactivation of the retinoblastoma protein. Here we show that overexpression of p16ink4 in certain cell types will lead to an arrest in the G1 phase of the cell cycle. In addition, we show that p16ink4 can only suppress the growth of human cells that contain functional pRB. Moreover, we have compared the effect of p16ink4 expression on embryo fibroblasts from wild-type and RB homozygous mutant mice. Wild-type embryo fibroblasts are inhibited by p16ink4, whereas the RB nullizygous fibroblasts are not. These data not only show that the presence of pRB is crucial for growth suppression by p16ink4 but also indicate that the pRB is the critical target acted upon by cyclin D-dependent kinases in the G1 phase of the cell cycle.
Insights
The tumor suppressor p16INK4 inhibits cyclin-dependent kinases 4 and 6, halting cell cycle progression. Its growth-suppressive function critically depends on the presence of a functional retinoblastoma protein (pRB).
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- p16INK4 is a known tumor suppressor frequently lost in human cancers.
- p16INK4 inhibits cyclin-dependent kinases 4 and 6 (CDK4/6).
- CDK4/6 can phosphorylate and inactivate the retinoblastoma protein (pRB), a key regulator of cell cycle progression.
Purpose of the Study:
- To investigate the role of p16INK4 in cell cycle regulation.
- To determine the mechanism by which p16INK4 exerts its tumor-suppressive function.
- To elucidate the critical target of p16INK4-mediated growth suppression.
Main Methods:
- Overexpression of p16INK4 in human cell lines.
- Comparison of p16INK4 effects on wild-type and retinoblastoma protein (pRB)-deficient mouse embryo fibroblasts.
- Cell cycle analysis.
Main Results:
- Overexpression of p16INK4 induced G1 phase arrest in susceptible cell types.
- p16INK4-mediated growth suppression was observed only in cells with functional pRB.
- RB-null mouse embryo fibroblasts were resistant to p16INK4-induced growth inhibition.
Conclusions:
- The retinoblastoma protein (pRB) is essential for p16INK4's tumor-suppressive activity.
- pRB is the critical target through which p16INK4, via CDK4/6 inhibition, regulates the G1 phase of the cell cycle.