Role of protein kinase C and the Sp1-p53 complex in activation of p21(WAF-1) expression by 12-O-tetradecanoylphorbol-13-acetate in human T cells.
Previous reports have shown that, in certain cell types, p21(WAF-1), which plays a central role in cell proliferation, can be activated by HTLV-I Tax protein and by TPA. Tax and TPA are also known to stimulate HTLV-I gene expression. Since cell proliferation has a major impact on HTLV-I replication, it was of interest to investigate their effect on p21(WAF-1) in human T cells, which are the main target of HTLV-I in human infection. This study demonstrates that p21(WAF-1) is activated in such cells by both factors, each acting through a different mechanism that does not influence the other. The effect of TPA is shown to require PKC activity. Notably, however, examination of different PKC isoforms revealed that PKC-alpha and PKC-epsilon stimulated p21(WAF-1) expression, whereas PKC-eta was rather inhibitory and PKC-beta1 and beta2 were ineffective. All these isoforms were found to be activated by TPA in the employed T cells, but this apparent paradox was resolved by the observation that when coexpressed together in these cells, the stimulatory PKCs override the inhibitory isoform. Further experiments demonstrated that the PKC-induced p21(WAF-1) activation was mediated by binding of Sp1-p53 complex to the second most upstream of the six Sp1 recognition sites present in its promoter and that this effect did not require the cooperation of an p53-binding site.
Schavinsky-Khrapunsky
Yana
Y
Department of Microbiology and Immunology, Cancer Research Center, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
Huleihel
Mahmoud
M
Aboud
Mordechai
M
Torgeman
Amram
A
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate