Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues.
Cell cycle progression from G(1) 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.
Ramsey
Matthew R
MR
Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295, USA.
Krishnamurthy
Janakiraman
J
Pei
Xin-Hai
XH
Torrice
Chad
C
Lin
Weili
W
Carrasco
Daniel R
DR
Ligon
Keith L
KL
Xiong
Yue
Y
Sharpless
Norman E
NE
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010879:Piperazines / Q000494:pharmacology; D010911:Pituitary Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology
C493972:Cdkn2c protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D010879:Piperazines; D011725:Pyridines; D051360:Cyclin-Dependent Kinase 5; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib