Human Papillomavirus E7 Repression in Cervical Carcinoma Cells Initiates a Transcriptional Cascade Driven by the Retinoblastoma Family, Resulting in Senescence
- 1 March 2007
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 81 (5), 2102-2116
- https://doi.org/10.1128/jvi.02348-06
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.This publication has 92 references indexed in Scilit:
- Apoptosis Inhibition by the Human DEK Oncoprotein Involves Interference with p53 FunctionsMolecular and Cellular Biology, 2006
- DEK Expression is Controlled by E2F and Deregulated in Diverse Tumor TypeCell Cycle, 2006
- E2 Proteins from High- and Low-Risk Human Papillomavirus Types Differ in Their Ability To Bind p53 and Induce Apoptotic Cell DeathJournal of Virology, 2006
- Oncogene-induced senescence as an initial barrier in lymphoma developmentNature, 2005
- Identification of Novel Target Genes of the Bone-Specific Transcription Factor Runx2Journal of Bone and Mineral Research, 2004
- New roles for the RB tumor suppressor proteinCurrent Opinion in Genetics & Development, 2004
- A Genomic Approach Reveals a Novel Mitotic Pathway in Papillomavirus CarcinogenesisCancer Research, 2004
- Biological activities and molecular targets of the human papillomavirus E7 oncoproteinOncogene, 2001
- Cooperative effect of antisense-Rb and antisense-p53 oligomers on the extension of life span in human diploid fibroblasts, TIG-1Biochemical and Biophysical Research Communications, 1991
- The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1ACell, 1988