title: SORBS2 and TLR3 induce premature senescence in primary human fibroblasts and keratinocytes.
abstract: BACKGROUND
  Genetic aberrations are required for the progression of HPV-induced cervical precancers. A prerequisite for clonal expansion of cancer cells is unlimited proliferative capacity. In a cell culture model for cervical carcinogenesis loss of genes located on chromosome 4q35→qter and chromosome 10p14-p15 were found to be associated with escape from senescence. Moreover, by LOH and I-FISH analyses a higher frequency of allele loss of these regions was also observed in cervical carcinomas as compared to CIN3. The aim of this study was to identify candidate senescence-related genes located on chromosome 4q35→qter and chromosome 10p14-p15 which may contribute to clonal expansion at the transition of CIN3 to cancer.
  
  
  METHODS
  Microarray expression analyses were used to identify candidate genes down-regulated in cervical carcinomas as compared to CIN3. In order to relate these genes with the process of senescence their respective cDNAs were overexpressed in HPV16-immortalized keratinocytes as well as in primary human fibroblasts and keratinocytes using lentivirus mediated gene transduction.
  
  
  RESULTS
  Overall fifteen genes located on chromosome 4q35→qter and chromosome 10p14-p15 were identified. Ten of these genes could be validated in biopsies by RT-PCR. Of interest is the novel finding that SORBS2 and TLR3 can induce senescence in primary human fibroblasts and keratinocytes but not in HPV-immortalized cell lines. Intriguingly, the endogenous expression of both genes increases during finite passaging of primary keratinocytes in vitro.
  
  
  CONCLUSIONS
  The relevance of the genes SORBS2 and TLR3 in the process of cellular senescence warrants further investigation. In ongoing experiments we are investigating whether this increase in gene expression is also characteristic of replicative senescence.
authors.forename: Melanie
authors.initials: M
authors.lastname: Liesenfeld
authors.forename: Sandy
authors.initials: S
authors.lastname: Mosig
authors.forename: Harald
authors.initials: H
authors.lastname: Funke
authors.forename: Lars
authors.initials: L
authors.lastname: Jansen
authors.forename: Ingo B
authors.initials: IB
authors.lastname: Runnebaum
authors.forename: Matthias
authors.initials: M
authors.lastname: Dürst
authors.affiliation: Department of Gynecology, Jena University Hospital, Friedrich Schiller University Jena, Bachstr, 18, Jena 07743, Germany. claudia.backsch@med.uni-jena.de.
authors.forename: Claudia
authors.initials: C
authors.lastname: Backsch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics*; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D002894:Chromosomes, Human, Pair 4; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D051196:Toll-Like Receptor 3 / Q000235:genetics* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D016601:RNA-Binding Proteins; C490755:SORBS2 protein, human; D051196:Toll-Like Receptor 3