Induction of transcription by p21Waf1/Cip1/Sdi1: role of NFkappaB and effect of non-steroidal anti-inflammatory drugs.
p21(Waf1/Cip1/Sdi1) is the primary mediator of cell cycle arrest in response to different forms of stress and in the programs of senescence and differentiation. p21 interacts with many regulatory proteins and has broad effects on cellular gene expression. p21 was previously shown to stimulate NFkappaB transcriptional activity through its effect on the p300/CBP transcription cofactor family. p21 expression in human cells increases mRNA levels of different genes, some of which have been implicated in carcinogenesis and age-related diseases. Here we report that p21 expression stimulates promoters of six p21-responsive human genes and the cytomegalovirus promoter, as well as an artificial promoter containing NFkappaB response elements. The IkappaBalpha super-repressor blocked the effect of p21 on all but one of the promoters, and the response to p21 was abrogated by the mutagenesis of an NFkappaB element. p21 inducibility of all the tested promoters and of the endogenous p21-responsive genes was strongly inhibited by adenoviral E1A protein and its deletion mutants that bind p300/CBP but not p21 or Rb. Sulindac and some other non-steroidal anti-inflammatory drugs that inhibit NFkappaB decrease the effects of p21 on the responsive promoters and endogenous genes. These findings suggest the feasibility of developing agents that will counteract p21-mediated induction of disease-associated genes.
Poole
Jason C
JC
Department of Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois, USA.
Thain
Alison
A
Perkins
Neil D
ND
Roninson
Igor B
IB
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D020672:I-kappa B Proteins / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013467:Sulindac / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
D017500:Adenovirus E1A Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D013467:Sulindac