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Human Papillomavirus E7 Repression in Cervical Carcinoma Cells Initiates a Transcriptional Cascade Driven by the Retinoblastoma Family, Resulting in Senescence
- Source :
- Journal of Virology. 81:2102-2116
- Publication Year :
- 2007
- Publisher :
- American Society for Microbiology, 2007.
-
Abstract
- This work demonstrates a central role for the retinoblastoma (Rb) family in driving the transcriptional program of induced and replicative senescence. HeLa cervical carcinoma cells rapidly undergo senescence when the human papillomavirus (HPV) type 18 E7 gene in these cells is repressed by the bovine papillomavirus (BPV) E2 protein. This senescence response requires the endogenous Rb pathway but not the p53 pathway. Microarray analysis 6 days after BPV E2 introduction into HeLa cells identified 224 cellular genes induced by E7 repression and 354 repressed genes. Many repressed genes were involved in cell cycle progression, and numerous induced genes encoded lysosomal proteins. These gene expression changes were blocked by constitutive expression of the wild-type HPV16 E7 or adenovirus E1A gene, but not by E7 or E1A mutants defective for Rb binding. Short hairpin RNAs targeting the Rb family also inhibited these gene expression changes and blocked senescence. Therefore, surprisingly, the transcriptional response to BPV E2 expression was entirely dependent on E7 repression and activation of the Rb family, and the BPV E2 protein did not directly affect the expression of cellular genes. Activation of the Rb family repressed E2F-responsive genes and stimulated transcriptional activators, thereby mobilizing multiple signals, such as repression of B-MYB and DEK, that were independently sufficient to induce senescence. There was extensive overlap between the transcriptional profiles of senescent, late-passage primary human fibroblasts and senescent cervical carcinoma cells, suggesting that this Rb family-mediated transcriptional cascade also plays a central role in replicative senescence.
- Subjects :
- Gene Expression Regulation, Viral
Senescence
Transcription, Genetic
viruses
Immunology
Uterine Cervical Neoplasms
Microbiology
Transformation and Oncogenesis
Viral Proteins
Virology
Gene expression
Animals
Humans
Genes, Retinoblastoma
Papillomaviridae
Gene
Psychological repression
Cellular Senescence
Oligonucleotide Array Sequence Analysis
Bovine papillomavirus
Genetics
Regulation of gene expression
Base Sequence
Human papillomavirus 18
biology
Microarray analysis techniques
Oncogene Proteins, Viral
biology.organism_classification
Cell biology
DNA-Binding Proteins
Insect Science
DNA, Viral
Cattle
Female
Cell aging
HeLa Cells
Signal Transduction
Subjects
Details
- ISSN :
- 10985514 and 0022538X
- Volume :
- 81
- Database :
- OpenAIRE
- Journal :
- Journal of Virology
- Accession number :
- edsair.doi.dedup.....98ae72b9426541634c6f97ce06f6a222