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Evidence for a Putative Senescence Gene Locus within the Chromosomal Region 10p14–p15¹

Gynäkologische Molekularbiologie, Abteilung Frauenheilkunde, Frauenklinik der Friedrich-Schiller-Universität Jena, 07743 Jena Germany [C. B., K. B., L. J., A. S., M. D.]; Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany [M. P., N. W.]; Gynäkologische Praxis, 89073 Ulm, Germany [R. K.]; and Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, California 92697-4025 [E. J. S.]

High-risk human papillomavirus (HPV) types 16 and 18 are involved in the multistep process of cervical cancer. Transfection of normal keratinocytes with high-risk HPV-DNA generally gives rise to immortal cultures. This may be explained by the loss of senescence genes as a consequence of HPV-induced genetic instability. On the basis of the dominance of cellular senescence over immortality, fusion of normal keratinocytes with HPV-immortalized cells results in complementation of these putative gene defects. In a previous study, we showed that underrepresentation of chromosome 10 is a characteristic phenomenon during the early phase of immortalization. Here we show that introduction of a normal copy of chromosome 10 into HPV16-immortalized cells (HPKII) by Microcell-mediated chromosome transfer resulted in senescence of a significant number of hybrids. By using several derivatives of chromosome 10 for further fusion experiments, the chromosomal region responsible for senescence could be assigned to 10p14–p15. The potential significance of loss of gene function in this region is underlined by the high frequency (38.7%) of loss of heterozygosity in cervical cancers including early stage tumors.

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