Induction of a cyclin/ cyclin-dependent kinase (CDK) inhibitory p21/Waf1/Cip1/Sid1 triggers growth arrest of normal and tumor ells in response in different types of damage and the onset of cellular senescence. p21 interacts not only with different cyclins and CDKs, but also with a large group of transcription factors, co-factors and regulators of signal transduction. The effects of ectopic p21 expression were investigated in that p21 induction leads to transcriptional activation of genes that have been implicated in several pathological conditions, including Alzheimer's disease, atherosclerosis, amyloidosis, arthritis and nephropathy, as well as susceptibility to oxidative stress. p21 also induces the expression of secreted mitogenic and anti-apoptotic factors with potentially tumor-promoting paracrine activities. Such activities have been associated with tumor-associated stromal fibroblasts and with senescent cells. The goal of the proposed program is to analyze the regulatory pathways that mediate the induction of disease-associated genes by p21 and to identify key factors, inhibition of which will interfere with the activation of such genes.
The first Aim of this program is to compare the effects of p21 and two other CDK inhibitors, p16/Ink4A and p217/Kip1, on gene expression in normal and transformed human fibroblasts.
The third Aim i s to delineate the domains of p21 responsible for the induction of transcription, through mutational analysis and selection of functionally active peptides of p21.
The final Aim of this program is to use a normalized human cDNA fragment library in a retroviral vector to select genetic suppressor elements (GSEs) that interfere with the activation of p21-inducible promoters Genes giving rise to such GSEs will be analyzed as likely mediators of the induction of transcription by p21. The products of such genes will provide potential targets for agents that may prevent p21- mediated induction of disease-associated genes.
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