Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues

Matthew R. Ramsey, Janakiraman Krishnamurthy, Xin Hai Pei, Chad Torrice, Weili Lin, Daniel R. Carrasco, Keith L. Ligon, Yue Xiong, Norman E. Sharpless

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

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 p16Ink4a and p18Ink4c showed similar growth kinetics as wild-type MEFs despite increased cdk4 activity. In vivo, germline deficiency of p16Ink4a and p18Ink4c resulted in increased proliferation in the intermediate pituitary and pancreatic islets of adult mice, and survival of p16Ink4a-/-;p18Ink4c-/- mice was significantly reduced due to aggressive pituitary tumors. Compensation among the Ink4 proteins was observed both in vivo in p18Ink4c-/- mice and in MEFs from p16 Ink4a-/-, p18Ink4c-/-, or p16Ink4a-/-;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 p16Ink4a and p18Ink4c coordinately regulate the in vivo catalytic activity of cdk4/6 in specific compartments of adult mice.

Original languageEnglish (US)
Pages (from-to)4732-4741
Number of pages10
JournalCancer Research
Volume67
Issue number10
DOIs
StatePublished - May 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Expression of p16<sup>Ink4a</sup> compensates for p18<sup>Ink4c</sup> loss in cyclin-dependent kinase 4/6-dependent tumors and tissues'. Together they form a unique fingerprint.

Cite this