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

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

Transcriptional regulation of downstream gene expression by thyroid hormone (T(3)) is mediated by the thyroid hormone receptor (TR). T(3) binding induces a complicated transition, where TR converts from a transcriptional repressor into a transcriptional activator and instigates downstream gene transcription. Binding of T(3) to TR also induces the degradation of TR, resulting in desensitization of the cells to further T(3) treatment. It has been shown that phosphorylation of TR plays a critical role in its activity and stability after T(3) binding. However, the kinases in control of phosphorylating TR in the nucleus have not been identified. In this study we demonstrate that MAPKs are possible candidates responsible for the nuclear phosphorylation of TR. Suppression of MAPKs with specific inhibitors repressed TR transcriptional activity and antagonized okadeic acid-induced TR transcriptional activity potentiation. Overexpression of the MAPK activator, MKK6, and its constitutively active mutant, MKK6EE, significantly increased TR activity and protected TR from degradation. Involvement of the 26S ubiquitin proteasome in hormone binding-induced TR degradation was also examined. We found that MAPKs enhanced the DNA binding affinity of TR. Our results suggest that MAPKs are the major kinases responsible for the nuclear phosphorylation of TR and are critical factors modulating the transcriptional activity and protein stability of TR subsequent to ligand binding.
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PMID:Mitogen-activated protein kinases potentiate thyroid hormone receptor transcriptional activity by stabilizing its protein. 1263 24

Type 3 (T3) effector proteins, secreted by nitrogen-fixing rhizobia with a bacterial T3 secretion system, affect the nodulation of certain host legumes. The open reading frame y4lO of Rhizobium sp. strain NGR234 encodes a protein with sequence similarities to T3 effectors from pathogenic bacteria (the YopJ effector family). Transcription studies showed that the promoter activity of y4lO depended on the transcriptional activator TtsI. Recombinant Y4lO protein expressed in Escherichia coli did not acetylate two representative mitogen-activated protein kinase kinases (human MKK6 and MKK1 from Medicago truncatula), indicating that YopJ-like proteins differ with respect to their substrate specificities. The y4lO gene was mutated in NGR234 (strain NGROmegay4lO) and in NGR Omega nopL, a mutant that does not produce the T3 effector NopL (strain NGR Omega nopLOmegay4lO). When used as inoculants, the symbiotic properties of the mutants differed. Tephrosia vogelii, Phaseolus vulgaris cv. Yudou No. 1, and Vigna unguiculata cv. Sui Qing Dou Jiao formed pink effective nodules with NGR234 and NGR Omega nopL Omega y4lO. Nodules induced by NGR Omega y4lO were first pink but rapidly turned greenish (ineffective nodules), indicating premature senescence. An ultrastructural analysis of the nodules induced by NGR Omega y4lO revealed abnormal formation of enlarged infection droplets in ineffective nodules, whereas symbiosomes harboring a single bacteroid were frequently observed in effective nodules induced by NGR234 or NGR Omega nopL Omega y4lO. It is concluded that Y4lO is a symbiotic determinant involved in the differentiation of symbiosomes. Y4lO mitigated senescence-inducing effects caused by the T3 effector NopL, suggesting synergistic effects for Y4lO and NopL in nitrogen-fixing nodules.
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PMID:Y4lO of Rhizobium sp. strain NGR234 is a symbiotic determinant required for symbiosome differentiation. 2629 32

Smooth muscle-rich tissues respond to mechanical overload by an adaptive hypertrophic growth combined with activation of angiogenesis, which potentiates their mechanical overload-bearing capabilities. Neovascularization is associated with mechanical strain-dependent induction of angiogenic factors such as CCN1, an immediate-early gene-encoded matricellular molecule critical for vascular development and repair. Here we have demonstrated that mechanical strain-dependent induction of the CCN1 gene involves signaling cascades through RhoA-mediated actin remodeling and the p38 stress-activated protein kinase (SAPK). Actin signaling controls serum response factor (SRF) activity via SRF interaction with the myocardin-related transcriptional activator (MRTF)-A and tethering to a single CArG box sequence within the CCN1 promoter. Such activity was abolished in mechanically stimulated mouse MRTF-A(-/-) cells or upon inhibition of CREB-binding protein (CBP) histone acetyltransferase (HAT) either pharmacologically or by siRNAs. Mechanical strain induced CBP-mediated acetylation of histones 3 and 4 at the SRF-binding site and within the CCN1 gene coding region. Inhibition of p38 SAPK reduced CBP HAT activity and its recruitment to the SRF.MRTF-A complex, whereas enforced induction of p38 by upstream activators (e.g. MKK3 and MKK6) enhanced both CBP HAT and CCN1 promoter activities. Similarly, mechanical overload-induced CCN1 gene expression in vivo was associated with nuclear localization of MRTF-A and enrichment of the CCN1 promoter with both MRTF-A and acetylated histone H3. Taken together, these data suggest that signal-controlled activation of SRF, MRTF-A, and CBP provides a novel connection between mechanical stimuli and angiogenic gene expression.
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PMID:Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase. 1954 62