Related Experiment Videos
CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary
D S Franklin1, V L Godfrey, H Lee
1Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Abstract:
INK4 and CIP/KIP are two distinct families of cyclin-dependent kinase (CDK) inhibitors implicated in mediating a wide range of cell growth control signals. We have created p18(INK4c)-deficient mice. These mice develop gigantism and widespread organomegaly. The pituitary gland, spleen, and thymus are disproportionately enlarged and hyperplastic. T and B lymphocytes develop normally in p18-deficient mice, but both exhibit increased cellularity and a higher proliferative rate upon mitogenic stimulation. Loss of p18, like that of p27, but not other CDK inhibitor genes, leads to a gradual progression from intermediate lobe pituitary hyperplasia in young mice to an adenoma by 10 months of age with a nearly complete penetrance. Mice lacking both p18 and p27, like mice chimeric for Rb deficiency, invariably died from pituitary adenomas by 3 months. Hence, p18 and p27 mediate two separate pathways to collaboratively suppress pituitary tumorigenesis, likely by controlling the function of Rb.
Insights
Mice lacking the p18 (INK4c) protein inhibitor developed gigantism and pituitary tumors. P18 and p27 collaboratively suppress pituitary tumor growth, highlighting their roles in cell cycle regulation.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Cyclin-dependent kinase (CDK) inhibitors regulate cell growth.
- INK4 and CIP/KIP are two main families of CDK inhibitors.
- These inhibitors are crucial for controlling cell proliferation signals.
Purpose of the Study:
- To investigate the role of p18 (INK4c) in cell growth and tumor suppression.
- To understand the collaborative function of p18 and p27 in preventing pituitary tumorigenesis.
Main Methods:
- Generation of p18 (INK4c)-deficient mice.
- Analysis of organ size, cellularity, and proliferation rates in knockout mice.
- Comparative study of mice lacking p18, p27, or both.
Main Results:
- p18-deficient mice exhibited gigantism and organomegaly, particularly in the pituitary, spleen, and thymus.
- Loss of p18 led to pituitary hyperplasia progressing to adenoma with high penetrance.
- Mice lacking both p18 and p27 died early from pituitary adenomas.
Conclusions:
- p18 (INK4c) is essential for suppressing pituitary tumor development.
- p18 and p27 act through separate pathways to collaboratively inhibit pituitary tumorigenesis.
- These CDK inhibitors likely control the function of Rb to prevent tumor formation.