PROTEASOME-DEPENDENT AND P53-DEPENDENT MASKING OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) FACTORS

Hepatoma Hep3B cell lines stably expressing a temperature-sensitive p5 3 species (p53-Val-135) displayed a reduced response to interleukin-6 (IL-6) when cultured at the wild-type (wt) p53 temperature (Wang, L., Ray anade, R., Garcia, D., Patel, K., Pan, H., and Sehgal, P. B. (1995 ) J. Biol. Chem, 270, 23159-23165). We now report that in such culture s IL-6 caused a rapid (20-30 min) and marked loss of cellular immunost aining for STAT3 and STAT5, but not for STAT1, The loss of STAT3 and S TAT5 immunostaining was transient (lasted 120 min) and tyrosine kinase dependent, and even though the loss was blocked by the proteasome inh ibitors MG132 and lactacystin it was not accompanied by changes in cel lular levels of STAT3 and STAT5 proteins suggesting that IL-6 triggere d a rapid masking but not degradation of these transcription factors, STAT3 and STAT5 masking was accompanied by a reduction in IL-B-induced nuclear DNA-binding activity, The data suggest that p53 may influence Jak-STAT signaling through a novel indirect mechanism involving a wt p53-dependent gene product which upon cytokine addition is activated i nto a ''STAT-masking factor'' in a proteasome dependent step.