This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pei, X.-H. Articles by Xiong, Y. Search for Related Content PubMed PubMed Citation Articles by Pei, X.-H. Articles by Xiong, Y.

p18^Ink4c Collaborates with Men1 to Constrain Lung Stem Cell Expansion and Suppress Non–Small-Cell Lung Cancers

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

Requests for reprints: Yue Xiong, Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, Program in Molecular Biology and Biotechnology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295. Phone: 919-962-2142; Fax: 919-966-8799; E-mail: yxiong{at}email.unc.edu.

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. [Cancer Res 2007;67(7):3162–70]

This article has been cited by other articles:

				V. Quereda and M. Malumbres Cell cycle control of pituitary development and disease J. Mol. Endocrinol., February 1, 2009; 42(2): 75 - 86. [Abstract] [Full Text] [PDF]

				D.M. Raiser, S.J. Zacharek, R.R. Roach, S.J. Curtis, K.W. Sinkevicius, D.W. Gludish, and C.F. Kim Stem Cell Biology in the Lung and Lung Cancers: Employing Pulmonary Context and Classic Approaches Cold Spring Harb Symp Quant Biol, November 26, 2008; (2008) sqb.2008.73.036v2. [Abstract] [PDF]

				D. J. Weiss, J. K. Kolls, L. A. Ortiz, A. Panoskaltsis-Mortari, and D. J. Prockop Stem Cells and Cell Therapies in Lung Biology and Lung Diseases Proceedings of the ATS, July 15, 2008; 5(5): 637 - 667. [Full Text] [PDF]

				C. D. Peacock and D. N. Watkins Cancer Stem Cells and the Ontogeny of Lung Cancer J. Clin. Oncol., June 10, 2008; 26(17): 2883 - 2889. [Abstract] [Full Text] [PDF]

				C. F. Kim Paving the road for lung stem cell biology: bronchioalveolar stem cells and other putative distal lung stem cells Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1092 - L1098. [Abstract] [Full Text] [PDF]

				P. Sicinski, S. Zacharek, and C. Kim Duality of p27Kip1 function in tumorigenesis Genes & Dev., July 15, 2007; 21(14): 1703 - 1706. [Full Text] [PDF]

				A. Besson, H. C. Hwang, S. Cicero, S. L. Donovan, M. Gurian-West, D. Johnson, B. E. Clurman, M. A. Dyer, and J. M. Roberts Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype Genes & Dev., July 15, 2007; 21(14): 1731 - 1746. [Abstract] [Full Text] [PDF]