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Expression of p16^Ink4a Compensates for p18^Ink4c Loss in Cyclin-Dependent Kinase 4/6–Dependent Tumors and Tissues

Departments of ¹ Medicine and Genetics, ² Biochemistry and Biophysics, and ³ Neurology and ⁴ Curriculum in Genetics and Molecular Biology, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina; ⁵ Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School; and ⁶ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts

Requests for reprints: Norman E. Sharpless, Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, CB# 7295, Chapel Hill, NC 27599-7295. Phone: 919-966-1185; Fax: 919-966-8212; E-mail: nes{at}med.unc.edu.

Cell cycle progression from G₁ to S phase depends on phosphorylation of pRb by complexes containing a cyclin (D type or E type) and cyclin-dependent kinase (e.g., cdk2, cdk4, or cdk6). Ink4 proteins function to oppose the action of cdk4/6-cyclin D complexes by inhibiting cdk4/6. We employed genetic and pharmacologic approaches to study the interplay among Ink4 proteins and cdk4/6 activity in vivo. Mouse embryo fibroblasts (MEF) lacking p16^Ink4a and p18^Ink4c showed similar growth kinetics as wild-type MEFs despite increased cdk4 activity. In vivo, germline deficiency of p16^Ink4a and p18^Ink4c resulted in increased proliferation in the intermediate pituitary and pancreatic islets of adult mice, and survival of p16^Ink4a–/–;p18^Ink4c–/– mice was significantly reduced due to aggressive pituitary tumors. Compensation among the Ink4 proteins was observed both in vivo in p18^Ink4c–/– mice and in MEFs from p16^Ink4a–/–, p18^Ink4c–/–, or p16^Ink4a–/–;p18^Ink4c–/– mice. Treatment with PD 0332991, a specific cdk4/6 kinase inhibitor, abrogated proliferation in those compartments where Ink4 deficiency was associated with enhanced proliferation (i.e., islets, pituitary, and B lymphocytes) but had no effect on proliferation in other tissues such as the small bowel. These data suggest that p16^Ink4a and p18^Ink4c coordinately regulate the in vivo catalytic activity of cdk4/6 in specific compartments of adult mice. [Cancer Res 2007;67(10):4732–41]

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