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Regulation of IL-6 Signaling by p53: STAT3- and STAT5-Masking in p53-Val¹³⁵-Containing Human Hepatoma Hep3B Cell Lines¹

Ravi J. Rayanade^*, MacKevin I. Ndubuisi^*, Joseph D. Etlinger^* and Pravin B. Sehgal^2,*,

Departments of ^* Cell Biology and Anatomy and Medicine, New York Medical College, Valhalla, NY 10595

The influence of p53 on cytokine-triggered Janus kinase-STAT signaling was investigated in human hepatoma Hep3B cell lines engineered to constitutively express the temperature-sensitive Val¹³⁵ mutant of p53. In comparison to the parental p53-free Hep3B cells, these p53-Val¹³⁵-containing Hep3B cell lines displayed a reduced response to IL-6 at the wild-type-like p53 temperature (32.5°C). In these cells, IL-6 induced a marked reduction in the immunologic accessibility of cytoplasmic and nuclear STAT3 and STAT5 within 20 to 30 min that lasted 2 to 4 h (STAT-masking) provided that the cells had been previously cultured at 32.5°C for at least 18 to 20 h. The onset of IL-6-induced STAT-masking required protein tyrosine kinase, protein tyrosine phosphatase, proteasomal, phospholipase C, and mitogen-activated protein kinase kinase 1 activities. The maintenance of IL-6-induced STAT-masking was dependent on continued signaling through the phosphatidylinositol-dependent phospholipase C pathway. Despite a reduction in IL-6-induced STAT3 DNA binding activity in the nuclear compartment during STAT-masking, there was increased and prolonged accumulation of tyrosine-phosphorylated STAT3 in both the cytoplasmic and nuclear compartments, indicating that the capacity of tyrosine-phosphorylated STAT3 to bind DNA was reduced during STAT-masking. Thus, IL-6-induced STAT-masking, as dramatically evident on immunomicroscopy, is a visible consequence of a novel cellular process by which a p53-Val¹³⁵-induced gene product(s) regulates the association of masking protein(s) with and the DNA-binding capacity of STAT3.

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