The G1-phase growth-arresting action of interleukin-1 is independent of p53 and p21/WAF1 function.
Interleukin-1 (IL-1) causes G1-phase growth arrest of A375-C6 human melanoma cells by hypophosphorylation of the retinoblastoma susceptibility gene product Rb. Because p53 and p21/WAF1 proteins are key components of growth arrest pathways involving Rb hypophosphorylation, we tested the functional role of these two proteins in IL-1 action. Exposure to IL-1 caused induction of both p53 and p21/WAF1 proteins. However, inhibition of p53 function by the K1 mutant of SV40-T antigen or by m175 (Arg to His) dominant-negative mutant of p53 did not result in abrogation of IL-1 action, suggesting that p53 function is not required for growth arrest by IL-1. Studies aimed at testing the role of p21/WAF1 in IL-1 action indicated that IL-1 induced p21/WAF1 expression independently of the p53 status of the cells. However, inhibition of p21/WAF1 expression resulted in only a marginal rescue from the growth-arresting action of IL-1. These findings imply that despite their induction, neither wild-type p53 nor p21 can fully account for the growth arrest by IL-1. Thus, a p53- and p21-independent pathway(s) mediates IL-1 action.
Nalca
A
A
Department of Microbiology and Immunology, Department of Surgery, Division of Urology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.
Rangnekar
V M
VM
D000906:Antibodies; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis*; D003593:Cytoplasm / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D000906:Antibodies; D000952:Antigens, Polyomavirus Transforming; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007375:Interleukin-1; D016159:Tumor Suppressor Protein p53