CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis.
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.
Franklin
D S
DS
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Godfrey
V L
VL
Lee
H
H
Kovalev
G I
GI
Schoonhoven
R
R
Chen-Kiang
S
S
Su
L
L
Xiong
Y
Y
D000236:Adenoma / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D001824:Body Constitution / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010911:Pituitary Neoplasms / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D013163:Splenomegaly / Q000209:etiology / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; C493961:Cdkn1b protein, mouse; C493972:Cdkn2c protein, mouse; D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases