Expression of p16Ink4a compensates for p18Ink4c loss in cyclin-dependent kinase 4/6-dependent tumors and tissues
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Updated: Jul 14, 2026
Analysis of Cell Cycle Position in Mammalian Cells
Published on: January 21, 2012
Matthew R Ramsey1, Janakiraman Krishnamurthy, Xin-Hai Pei
1Department of Medicine, The Lineberger Comprehensive Cancer Center, The University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7295, USA.
Abstract:
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.
Insights
Ink4 proteins p16 and p18 coordinate to regulate cyclin-dependent kinase 4/6 (cdk4/6) activity in adult mice. Loss of these proteins leads to increased proliferation and aggressive tumors, highlighting their tumor suppressor roles.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Cell cycle progression relies on cyclin-dependent kinases (cdks) and their inhibitors, Ink4 proteins.
- Ink4 proteins, such as p16 and p18, specifically inhibit cdk4/6-cyclin D complexes, regulating the G1 to S phase transition.
Purpose of the Study:
- To investigate the in vivo interplay between Ink4 proteins and cdk4/6 activity.
- To determine the functional redundancy and compensatory mechanisms among Ink4 proteins in vivo.
- To assess the impact of Ink4 deficiency on cell proliferation and tumor formation.
Main Methods:
- Genetic manipulation: generation of mice deficient in p16(Ink4a) and p18(Ink4c).
- Pharmacological inhibition: use of PD 0332991, a specific cdk4/6 kinase inhibitor.
- Analysis of cell proliferation in various tissues (pituitary, pancreatic islets, B lymphocytes, small bowel) and tumor development.
Main Results:
- MEFs lacking p16(Ink4a) and p18(Ink4c) showed normal growth kinetics despite elevated cdk4 activity, suggesting compensatory mechanisms.
- In vivo, combined deficiency of p16(Ink4a) and p18(Ink4c) led to increased proliferation in the pituitary and pancreatic islets.
- Mice lacking both p16(Ink4a) and p18(Ink4c) developed aggressive pituitary tumors and had reduced survival.
- PD 0332991 treatment inhibited proliferation in Ink4-deficient compartments but not in other tissues.
- Evidence of Ink4 protein compensation was observed both in vivo and in vitro.
Conclusions:
- p16(Ink4a) and p18(Ink4c) function coordinately to regulate cdk4/6 activity in specific adult mouse tissues.
- Ink4 proteins act as critical tumor suppressors, and their combined loss can drive aggressive tumorigenesis.
- Pharmacological inhibition of cdk4/6 can counteract the proliferative effects of Ink4 deficiency in specific contexts.
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