p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumors.
Mutant mice lacking both cyclin-dependent kinase (CDK) inhibitors p18(Ink4c) and p27(Kip1) develop a tumor spectrum reminiscent of human multiple endocrine neoplasia (MEN) syndromes. To determine how p18 and p27 genetically interact with Men1, the tumor suppressor gene mutated in familial MEN1, we characterized p18-Men1 and p27-Men1 double mutant mice. Compared with their corresponding single mutant littermates, the p18(-/-); Men1(+/-) mice develop tumors at an accelerated rate and with an increased incidence in the pituitary, thyroid, parathyroid, and pancreas. In the pituitary and pancreatic islets, phosphorylation of the retinoblastoma (Rb) protein at both CDK2 and CDK4/6 sites was increased in p18(-/-) and Men1(+/-) cells and was further increased in p18(-/-); Men1(+/-) cells. The remaining wild-type Men1 allele was lost in most tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-); Men1(+/-) mice. Combined mutations of p27(-/-) and Men1(+/-), in contrast, did not exhibit noticeable synergistic stimulation of Rb kinase activity, cell proliferation, and tumor growth. These results demonstrate that functional collaboration exists between p18 and Men1 and suggest that Men1 may regulate additional factor(s) that interact with p18 and p27 differently.
Bai
Feng
F
Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.
Pei
Xin-Hai
XH
Nishikawa
Toru
T
Smith
Matthew D
MD
Xiong
Yue
Y
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D048429:Cell Size; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000172:deficiency / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D018358:Neuroendocrine Tumors / Q000473:pathology*; D010766:Phosphorylation; D010902:Pituitary Gland / Q000166:cytology / Q000473:pathology; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism
D050763:Cyclin-Dependent Kinase Inhibitor p18; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases