Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a genetic strategy designed to find proteins involved in the function of the Saccharomyces cerevisiae transcriptional activator GAL4, we isolated mutants in two genes which rescue a class of gal4 activation domain mutants. One of these genes, SUG1, encodes a member of a large family of putative ATPases, the Conserved ATPase containing Domain (CAD) proteins (also known as AAA proteins) that are involved in a wide variety of cellular functions. Subsequently, SUG1 was identified as a subunit of the 26 S proteasome. We have now cloned the gene defined by the second complementation group. SUG2 encodes an essential 49-kDa protein that is also a member of the CAD family and is 43% identical to SUG1. The mutation in sug2-1, like that in sug1-1, is found in the CAD near the highly conserved ATPase motif. We present biochemical and genetic evidence that SUG2 is associated in vivo with SUG1 and is a novel CAD protein subunit of the 26 S proteasome. With its highly conserved mammalian homologs, human p42 and ground squirrel CADp44, SUG2 defines a new class of proteasomal CAD proteins.
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PMID:Isolation and characterization of SUG2. A novel ATPase family component of the yeast 26 S proteasome. 895 18

Because both the brain natriuretic peptide (BNP) gene and the cytokine interleukin-1beta (IL-1beta) are induced in the infarcted myocardium, localized production of IL-1beta may regulate the BNP gene. We tested whether (1) IL-1beta regulates the human BNP promoter, (2) cis elements in the proximal promoter respond to IL-1beta, and (3) mitogen-activated protein kinase (MAPK) signaling pathways [p42/44, c-jun (JNK) and p38 kinase] are involved. We transferred the hBNP promoter coupled to a luciferase reporter gene or constructs with mutations in the proximal promoter GATA and M-CAT elements into neonatal rat ventricular myocytes and treated the cells with IL-1beta for 24 hours. IL-1beta-stimulated hBNP luciferase activity was eliminated by pretreatment with the transcription inhibitor actinomycin D. Both the p38 kinase inhibitor SB205380 (SB) and cotransfection of a dominant-negative mutant of p38 kinase reduced IL-1beta stimulation of the hBNP promoter. Dominant-negative mutants of Ras and Rac inhibited IL-1beta-stimulated hBNP luciferase activity by 64% and 90%, respectively. Constitutively active forms of Rac and MKK6, the immediate upstream activator of p38, were stimulatory; however, only the effect of MKK6 was inhibited by SB. Neither the p42/44 nor the JNK pathway was involved in the action of IL-1beta. Both IL-1beta and MKK6 activation of the hBNP promoter were partially reduced when the promoter contained a mutated M-CAT element. In summary, (1) IL-1beta is a transcriptional activator of the hBNP promoter; (2) IL-1beta acts through a Ras-dependent pathway not coupled to activation of p42/44 MAPK or JNK; (3) IL-1beta acts through a Rac-dependent pathway, but the downstream effector is not known; and (4) IL-1beta activation of p38 kinase is partially involved in regulation of the hBNP promoter, targeting the proximal M-CAT element.
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PMID:Interleukin-1beta regulation of the human brain natriuretic peptide promoter involves Ras-, Rac-, and p38 kinase-dependent pathways in cardiac myocytes. 993 Nov 18

Hypoxia-inducible factor 1 (HIF-1) is the key transcriptional activator of hypoxia-inducible genes and an important anti-cancer target. Its regulated subunit, HIF-1alpha, is controlled by oxygen levels and major signaling pathways. We reported previously that phosphorylation of Ser(641/643) by p42/44 MAPK is essential for HIF-1alpha nuclear accumulation and activity. We now show that a fragment of HIF-1alpha (amino acids 616-658), termed MAPK target domain, contains a nuclear export signal (NES), which has atypical hydrophobic residue spacing. Localization, reporter gene, and co-immunoprecipitation assays demonstrate that the identified NES interacts with CRM1 in a phosphorylation-sensitive manner. Furthermore, disruption of the NES (I637A/L638A/I639A) restores nuclear localization and activity of nonphosphorylated HIF-1alpha and renders it largely resistant to inhibition of MAPK, an effect reproduced by a phosphomimetic mutation (S641E). As these data predict, overexpression of wild-type or mutant (S641A/S643A) MAPK target domain in HeLa cells modulates the activity and subcellular distribution of endogenous HIF-1alpha. We suggest that control of HIF-1alpha nuclear transport represents an important MAPK-dependent regulatory mechanism.
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PMID:Atypical CRM1-dependent nuclear export signal mediates regulation of hypoxia-inducible factor-1alpha by MAPK. 1868 85

Despite several decades of efforts to develop safer, efficacious, and non-addictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine. Morphine and endogenous mu opioid peptides exert their pharmacological actions mainly through the mu opioid receptor (MOR). Analgesic effects of opioids in animals are dependent on the MOR expression levels, as demonstrated by studies of MOR-knockout mice (homo/heterozygotes) and MOR-less expressing mice. Surprisingly, in the course of our investigation to understand the mechanisms involved in the regulation of MOR gene expression, cycloheximide (CHX), a known protein synthesis inhibitor, markedly induced accumulation of MOR mRNAs in both MOR-negative and -positive cells. This induction was blocked by inhibitors of phosphoinositide 3-kinase (PI3-K) and p38 MAPK, but not by a p42/44 MAPK inhibitor. In vitro, CHX was found to activate the MOR promoter and this activation was suppressed by inhibition of PI3-K. The transcriptional activator Sox18 was recruited to the MOR promoter in CHX-treated cells and this recruitment was also inhibited by the PI3-K and p38 MAPK inhibitors, Ly294002 and SB203580, respectively. Consistently, acetylation of histone H3 and induction of H3-K4 methylation were detected while reductions of histone deacetylase 2 binding and H3-K9 methylation were observed on the promoter. Furthermore, the MOR mRNA accumulation was almost completely inhibited in the presence of actinomycin-D, indicating that this effect occurs mainly through activation of the transcriptional machinery. These observations suggest that CHX directly induces MOR gene transcription by recruiting the active transcription factor Sox18 to the MOR promoter through PI3- and/or p38 MAPK pathways.
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PMID:p38 mitogen-activated protein kinase and PI3-kinase are involved in up-regulation of mu opioid receptor transcription induced by cycloheximide. 2119 37