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J Biol Chem, Vol. 274, Issue 42, 29874-29882, October 15, 1999

STAT5b Down-regulates Peroxisome Proliferator-activated Receptor  Transcription by Inhibition of Ligand-independent Activation Function Region-1 trans-Activation Domain

From the Division of Cell and Molecular Biology, Department of Biology, Boston University, Boston, Massachusetts 02215

Growth hormone-activated STAT5b inhibits by up to 80% the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) , a nuclear receptor activated by diverse environmental chemicals and hypolipidemic drugs classified as peroxisome proliferators. This inhibitory cross-talk between STAT5b and PPAR is now reported for PPAR forms  and  and for thyroid hormone receptor, indicating a more general potential for inhibitory cross-talk between JAK/STAT and nuclear receptor signaling pathways. Further investigations revealed that SOCS-3, a growth hormone-inducible negative regulator of cytokine signaling to STAT5b, abolished the STAT5b inhibitory response. A constitutively active STAT5b mutant failed to inhibit PPAR activity, indicating that STAT5b does not induce synthesis of a more proximal PPAR inhibitor. STAT5b inhibition was not reversed by overexpression of the heterodimerization partner of PPAR (retinoid X receptor) or the nuclear receptor coactivators P300 and SRC-1, suggesting that STAT5b does not inhibit PPAR by competing for these limiting cellular cofactors. STAT5b did not inhibit a chimeric receptor comprised of yeast GAL4 DNA-binding domain linked to the ligand binding/AF-2 trans-activation domain of PPAR, indicating that the COOH-terminal AF-2 domain of PPAR is not the target of STAT5b inhibition. Rather, STAT5b inhibited transcription driven by the NH₂-terminal ligand-independent AF-1 trans-activation domain of PPAR in a GAL4-linked chimera by ~80%. The conservation of this AF-1 trans-activation function in many nuclear receptors suggests that AF-1 may serve as an important target for inhibitory cross-talk between STAT transcription factors and nuclear receptors in a variety of signaling pathways.

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