Two posttranscriptional pathways that regulate p21(Cip1/Waf1/Sdi1) are identified by HPV16-E6 interaction and correlate with life span and cellular senescence.
The p21((Cip1/Waf1/Sdi1)) protein is a cyclin-dependent kinase inhibitor that is induced in normal human fibroblasts (NHF) following DNA damage, following serum stimulation, and at cellular senescence. Expression of the human papilloma virus 16 E6 oncoprotein in NHF cells results in the loss of the p21 protein, independent of mRNA level under most conditions. The p21 protein levels in NHF-E6 cells remained low following DNA damage or serum stimulation even though mRNA levels increased. In contrast, the p21 protein was transiently induced in NHF-E6 cells at the onset of cellular senescence. Expression of the E6 oncoprotein in transformed cells had no effect on p21 protein levels. This demonstrates that two posttranscriptional pathways regulate expression of p21 protein in NHF cells under different conditions. Disruption of posttranscriptional regulation is correlated with extension of life span, altered cell fate, and transformation.
Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Science, Research Triangle Park, North Carolina, 27709, USA.
B A
BA
Burkhart
D A
DA
Alcorta
C
C
Chiao
J S
JS
Isaacs
J C
JC
Barrett
D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000502:physiology*; D027383:Papillomaviridae / Q000502:physiology; D012313:RNA / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012097:Repressor Proteins
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D012313:RNA