Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The androgen receptor (AR) is a nuclear hormone receptor superfamily member that conveys both trans repression and ligand-dependent trans-activation function. Activation of the AR by dihydrotestosterone (DHT) regulates diverse physiological functions including secondary sexual differentiation in the male and the induction of apoptosis by the JNK kinase, MEKK1. The AR is posttranslationally modified on lysine residues by acetylation and sumoylation. The histone acetylases p300 and P/CAF directly acetylate the AR in vitro at a conserved KLKK motif. To determine the functional properties governed by AR acetylation, point mutations of the KLKK motif that abrogated acetylation were engineered and examined in vitro and in vivo. The AR acetylation site point mutants showed wild-type trans repression of NF-kappa B, AP-1, and Sp1 activity; wild-type sumoylation in vitro; wild-type ligand binding; and ligand-induced conformational changes. However, acetylation-deficient AR mutants were selectively defective in DHT-induced trans activation of androgen-responsive reporter genes and coactivation by SRC1, Ubc9, TIP60, and p300. The AR acetylation site mutant showed 10-fold increased binding of the N-CoR corepressor compared with the AR wild type in the presence of ligand. Furthermore, histone deacetylase 1 (HDAC1) bound the AR both in vivo and in cultured cells and HDAC1 binding to the AR was disengaged in a DHT-dependent manner. MEKK1 induced AR-dependent apoptosis in prostate cancer cells. The AR acetylation mutant was defective in MEKK1-induced apoptosis, suggesting that the conserved AR acetylation site contributes to a pathway governing prostate cancer cellular survival. As AR lysine residue mutations that abrogate acetylation correlate with enhanced binding of the N-CoR repressor in cultured cells, the conserved AR motif may directly or indirectly regulate ligand-dependent corepressor disengagement and, thereby, ligand-dependent trans activation.
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PMID:Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. 1197 70

N-CoR and SMRT are corepressor paralogs that partner with and mediate transcriptional repression by a wide variety of metazoan transcription factors, including nuclear hormone receptors. Although encoded by distinct genetic loci, N-CoR and SMRT share substantial sequence interrelatedness, form analogous assemblies with histone deacetylases and auxiliary factors, can interact with overlapping sets of transcription factor partners, and exert overlapping functions in cells. SMRT is subject to negative regulation by MAPK signaling pathways operating downstream of growth factor and stress signaling pathways. We report here that whereas activation of MEKK1 leads to phosphorylation of SMRT, its dissociation from its transcription factor partners in vivo and in vitro, and its redistribution from the cell nucleus to a cytoplasmic compartment, N-CoR is refractory to all these forms of regulation. In contrast to this MAPK cascade, other signal transduction pathways operating downstream of growth factor/cytokine receptors appear able to affect both corepressor paralogs. Our results indicate that SMRT and N-CoR are embedded in distinct regulatory networks and that the two corepressors interpret growth factor, cytokine, differentiation, and prosurvival signals differently.
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PMID:SMRT and N-CoR corepressors are regulated by distinct kinase signaling pathways. 1549 94

Defining the precise molecular strategies that coordinate patterns of transcriptional responses to specific signals is central for understanding normal development and homeostasis as well as the pathogenesis of hormone-dependent cancers. Here we report specific prostate cancer cell/macrophage interactions that mediate a switch in function of selective androgen receptor antagonists/modulators (SARMs) from repression to activation in vivo. This is based on an evolutionarily conserved receptor N-terminal L/HX7LL motif, selectively present in sex steroid receptors, that causes recruitment of TAB2 as a component of an N-CoR corepressor complex. TAB2 acts as a sensor for inflammatory signals by serving as a molecular beacon for recruitment of MEKK1, which in turn mediates dismissal of the N-CoR/HDAC complex and permits derepression of androgen and estrogen receptor target genes. Surprisingly, this conserved sensor strategy may have arisen to mediate reversal of sex steroid-dependent repression of a limited cohort of target genes in response to inflammatory signals, linking inflammatory and nuclear receptor ligand responses to essential reproductive functions.
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PMID:Macrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. 1646 93