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 language | English |
|---|---|
| Pages (from-to) | 4732-4741 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 67 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 15 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues. / Ramsey, Matthew R.; Krishnamurthy, Janakiraman; Pei, Xin-Hai; Torrice, Chad; Lin, Weili; Carrasco, Daniel R.; Ligon, Keith L.; Xiong, Yue; Sharpless, Norman E.
In: Cancer Research, Vol. 67, No. 10, 15.05.2007, p. 4732-4741.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues
AU - Ramsey, Matthew R.
AU - Krishnamurthy, Janakiraman
AU - Pei, Xin-Hai
AU - Torrice, Chad
AU - Lin, Weili
AU - Carrasco, Daniel R.
AU - Ligon, Keith L.
AU - Xiong, Yue
AU - Sharpless, Norman E.
PY - 2007/5/15
Y1 - 2007/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34250372017&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34250372017&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-06-3437
DO - 10.1158/0008-5472.CAN-06-3437
M3 - Article
C2 - 17510401
AN - SCOPUS:34250372017
VL - 67
SP - 4732
EP - 4741
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 10
ER -