Evidence for a putative senescence gene locus within the chromosomal region 10p14-p15.
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.
Poignée
M
M
Gynäkologische Molekularbiologie, Abteilung Frauenheilkunde, Frauenklinik der Friedrich-Schiller-Universität Jena, 07743 Jena, Germany.
Backsch
C
C
Beer
K
K
Jansen
L
L
Wagenbach
N
N
Stanbridge
E J
EJ
Kirchmayr
R
R
Schneider
A
A
Dürst
M
M
D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000821:virology; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D016922:Cellular Senescence / Q000235:genetics*; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology / Q000821:virology; D019656:Loss of Heterozygosity; D027383:Papillomaviridae / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000473:pathology / Q000821:virology
D004279:DNA, Viral