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Cell Growth & Differentiation Vol. 10, 27-33, January 1999
© 1999 American Association for Cancer Research

Deletion of p16INK4A/CDKN2 and p15INK4B in Human Somatic Cell Hybrids and Hybrid-derived Tumors1

Steven J. Kuerbitz2, Jennifer Malandro, Nicole Compitello, Stephen B. Baylin and Jeremy R. Graff3

Departments of Pediatrics [S. J. K., J. M., N. C.] and Genetics [S. J. K.] and The Ireland Cancer Center [S. J. K.], Case Western Reserve University School of Medicine, Cleveland, Ohio 44106; and The Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 [S. B. B., J. R. G.]

Deletion or epigenetic inactivation of the tumor suppressor gene p16INK4A/CDKN2 (p16) has been observed in multiple human tumors. We assayed hybrid cell lines between human diploid fibroblasts and fibrosarcoma cells for p16 allelic status and expression and found that p16 was expressed in the parental diploid fibroblast cell lines used, whereas the parental fibrosarcoma cell line HT1080.6TG exhibited homozygous deletion of p16. Most immortalized hybrid cell lines derived from these parent cell lines, whether tumorigenic or nontumorigenic, exhibited loss of fibroblast-derived p16 alleles. All p16-negative hybrid cell lines also exhibited deletion of p15INK4B (p15). Hybrid cell lines yielded tumors upon s.c. injection into athymic nude mice regardless of p16/p15 status. Tumors derived from six p16/p15-positive hybrid cells, however, revealed deletions of both p16 and p15. When human diploid fibroblasts were fused with A388.6TG squamous cell carcinoma cells, which exhibit aberrant methylation of p16, the resulting hybrids again exhibited deletion of the unmethylated fibroblast-derived p16 alleles. Transfection of both HT1080.6TG and A388.6TG cells with wild-type p16 expression vector resulted in decreased clonogenicity in culture. Although the determinants directing genetic versus epigenetic inactivation of p16 and p15 remain unclear, these results demonstrate that p16-mediated growth suppression could be abrogated by either mechanism in somatic cell hybrids.




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S. Nishizuka, H. Tsujimoto, and E. J. Stanbridge
Detection of Differentially Expressed Genes in HeLa Fibroblast Hybrids Using Subtractive Suppression Hybridization
Cancer Res., June 1, 2001; 61(11): 4536 - 4540.
[Abstract] [Full Text] [PDF]




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Cancer Research Clinical Cancer Research
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Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1999 by the American Association of Cancer Research.