Abstract
Growth hormone-activated STAT5b inhibits by up to 80% the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) alpha, 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 gamma and delta 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 PPARalpha activity, indicating that STAT5b does not induce synthesis of a more proximal PPARalpha 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 PPARalpha 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 PPARalpha, indicating that the COOH-terminal AF-2 domain of PPAR is not the target of STAT5b inhibition. Rather, STAT5b inhibited transcription driven by the NH(2)-terminal ligand-independent AF-1 trans-activation domain of PPARalpha in a GAL4-linked chimera by approximately 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.
Highlights
peroxisome proliferator-activated receptor (PPAR) are transcription factors that belong to the nuclear receptor superfamily, and, like other nuclear receptors, they contain conserved domains that function in DNA binding, ligand binding, transcriptional activation, and dimerization
GH-activated STAT5b inhibits the transcriptional activation of PPAR␣ by structurally diverse peroxisome proliferators [22], suggesting a mechanism whereby hormones and cytokines that activate STAT5b [2] may inhibit the pleiotropic responses of liver and perhaps other tissues to the numerous environmental chemicals, hypolipidemic agents, and other structurally diverse chemicals that are classified as peroxisome proliferators [13]
The present study reports that GH exerts inhibitory effect on PPAR␥, PPAR␦, and T3R transcriptional activity
Summary
PPARs are transcription factors that belong to the nuclear receptor superfamily, and, like other nuclear receptors, they contain conserved domains that function in DNA binding, ligand binding, transcriptional activation, and dimerization (reviewed in Refs. 8 and 9). A wide variety of structurally distinct PPAR ligands have been identified These include certain environmental chemicals, fibrate hypolipidemic drugs, fatty acids, and eicosanoids for PPAR␣; anti-diabetic thiazolidinediones and 15-deoxy-⌬12,14 prostaglandin J2 for PPAR␥; and the fatty acid-like compound L631033 for PPAR␦ [11, 12]. This diverse spectrum of PPAR ligands suggests that these receptors mediate a wide variety of biological functions. We previously demonstrated that activation of STAT5b signaling by either GH or prolactin inhibits, by up to 80%, PPAR␣-dependent reporter gene transcription stimulated by both endogenous and foreign chemical peroxisome proliferators [22]. Our findings suggest that STAT5b inhibition of PPAR transcriptional activity proceeds via a novel mechanism that involves the NH2-terminal AF-1 trans-activation domain of the nuclear receptor, which serves as the target for insulin stimulation of PPAR␣ activity [29], albeit by a distinct mechanism
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