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Molecular and Cellular Biology, February 2003, p. 1269-1277, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1269-1277.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Haploinsufficiency of p18INK4c Sensitizes Mice to Carcinogen-Induced Tumorigenesis

Feng Bai,1 Xin-Hai Pei,1 Virginia L. Godfrey,2 and Yue Xiong1,3*

Lineberger Comprehensive Cancer Center,1 Department of Pathology and Laboratory Medicine,2 Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-72953

Received 24 September 2002/ Returned for modification 5 November 2002/ Accepted 18 November 2002

The INK4 family of cyclin-dependent kinase (CDK) inhibitors negatively regulates cyclin D-dependent CDK4 and CDK6 and thereby retains the growth-suppressive function of Rb family proteins. Mutations in the CDK4 gene conferring INK4 resistance are associated with familial and sporadic melanoma in humans and result in a wide spectrum of tumors in mice. Whereas loss of function of other INK4 genes in mice leads to little or no tumor development, targeted deletion of p18INK4c causes spontaneous pituitary tumors and lymphoma late in life. Here we show that treatment of p18 null and heterozygous mice with a chemical carcinogen resulted in tumor development at an accelerated rate. The remaining wild-type allele of p18 was neither mutated nor silenced in tumors derived from heterozygotes. Hence, p18 is a haploinsufficient tumor suppressor in mice.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, Campus Box 7295, The 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.

Molecular and Cellular Biology, February 2003, p. 1269-1277, Vol. 23, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.4.1269-1277.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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