p18Ink4c collaborates with Men1 to constrain lung stem cell expansion and suppress non-small-cell lung cancers.
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 and showed that p18, but not p27, functionally collaborates with Men1 in suppressing lung tumorigenesis. Lung tumors developed in both Men1(+/-) and p18(-/-);Men1(+/-) mice at a high penetrance and contain both neuroendocrine and nonneuroendocrine cells. The remaining wild-type Men1 allele was lost in most lung tumors from Men1(+/-) mice but was retained in most tumors from p18(-/-);Men1(+/-) mice, showing a functional collaboration between p18 and Men1 in lung tumor suppression. Phosphorylation of Rb protein at both CDK2 and CDK4/CDK6 sites were significantly increased in normal bronchial epithelia and tumor cells derived from p18(-/-);Men1(+/-) mice compared to those from single p18(-/-) or Men1(+/-) mice. Lung tumors developed in p18(-/-);Men1(+/-) mice were multifocal, more heterogeneous, and highly invasive compared to those developed in either p18(-/-) or Men1(+/-) mice. Bronchioalveolar stem cells are expanded in normal and tumorigenic lungs of p18(-/-) mice and are further expanded in p18(-/-);Men1(+/-) lung tumors. These results reveal a previously unrecognized function of p18 in lung tumor suppression through collaboration with Men1 to control lung stem cell proliferation.
Pei
Xin-Hai
XH
Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Bai
Feng
F
Smith
Matthew D
MD
Xiong
Yue
Y
D000483:Alleles; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000172:deficiency / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D016147:Genes, Tumor Suppressor; D007178:Inbreeding; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013234:Stem Cells / Q000473:pathology* / Q000502:physiology
C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein