Deep research summary for GADD45G using Falcon/Edison Scientific Literature
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GADD45G functions as a stress sensor and adaptor that integrates stress signals to regulate cell-cycle checkpoints, apoptosis/survival decisions, and stress-activated kinase pathways.
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GADD45G inhibits CDK1/cyclin B1 kinase activity, contributing to S and G2/M checkpoint control following genotoxic stress.
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GADD45G can activate the upstream MAP3K4/MTK1 (MEKK4) to stimulate p38 and JNK MAPK signaling, especially in immune contexts.
Gene Ontology annotation through association of InterPro records with GO terms.
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods.
A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK.
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Identified GADD45alpha, beta, and gamma as activators of MTK1/MEKK4 that mediate p38/JNK activation in response to environmental stresses including UV radiation and chemical mutagens.
"three related proteins, GADD45alpha (= GADD45), GADD45, (= MyD118), and GADD45gamma, were identified that bound to an N-terminal domain of MTK1. These proteins activated MTK1 kinase activity, both in vivo and in vitro. The GADD45-like genes are induced by environmental stresses, including MMS, UV, and gamma irradiation."
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Showed that GADD45 expression induces apoptosis that can be partially suppressed by dominant-negative MTK1.
"Expression of the GADD45-like genes induces p38/JNK activation and apoptosis, which can be partially suppressed by coexpression of a dominant inhibitory MTK1 mutant protein."
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GADD45 proteins mediate activation of the p38/JNK pathway via MTK1/MEKK4.
"We propose that the GADD45-like proteins mediate activation of the p38/JNK pathway, via MTK1/ MEKK4, in response to environmental stresses."
Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding.
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GADD45 proteins bind to a site in MTK1 near the N-terminal autoinhibitory domain and relieve autoinhibition, allowing interaction with substrate MKK6.
"GADD45 proteins bind a site in MTK1 near the inhibitory domain and relieve autoinhibition. Mutants of full-length MTK1 were isolated that can interact with MKK6 in the absence of the activator GADD45 proteins."
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Functional complementation screening identified GADD45 proteins as specific MTK1 activators.
"By a functional complementation screening with yeast cells, GADD45 proteins (GADD45alpha, beta, and gamma) were identified as MTK1 activators."
CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle.
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CRIF1 (GADD45GIP1) interacts with all three GADD45 family proteins in the nucleus.
"CRIF1 binds specifically to the Gadd45 family proteins, as determined by an in vitro glutathione S-transferase pull-down assay and an in vivo mammalian cell two-hybrid assay along with coimmunoprecipitation assays."
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CRIF1 and GADD45 proteins have additive inhibitory effects on cdc2/cyclin B1 and cdk2/cyclin E kinase activity.
"Recombinant CRIF1 inhibits the histone H1 kinase activity of immunoprecipitated Cdc2-cyclin B1 and Cdk2-cyclin E, and the inhibitory effects were additive with Gadd45 proteins."
GADD45γ regulates the thermogenic capacity of brown adipose tissue.
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GADD45G is induced by cold/norepinephrine in brown adipose tissue and activates p38 MAPK, which then activates ERRbeta/gamma transcriptional function.
"GADD45gamma works by activating MAPK p38, which is a potent activator of ERRbeta and ERRgamma transcriptional function."
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Gadd45g knockout mice have defects in UCP1 induction and thermogenic response to cold.
"Mice lacking Gadd45gamma have defects in Ucp1 induction and the thermogenic response to cold."
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GADD45G/p38/ERRgamma represents a novel pathway regulating BAT thermogenesis.
"Our findings elucidate a previously unidentified GADD45gamma/p38/ERRgamma pathway that regulates BAT thermogenesis and may enable new approaches for the stimulation of energy expenditure."
A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease.
Towards a proteome-scale map of the human protein-protein interaction network.
A directed protein interaction network for investigating intracellular signal transduction.
Toward an understanding of the protein interaction network of the human liver.
A proteome-scale map of the human interactome network.
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
A reference map of the human binary protein interactome.
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
Crystal structure of human Gadd45γ [corrected] reveals an active dimer.
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GADD45G forms homodimers through a four-helix bundle interface involving conserved helices alpha2 and alpha3.
"a unique dimer formed via a bundle of four parallel helices, involving the most conserved residues among the Gadd45 isoforms."
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Dimerization is required for growth-inhibitory activity and apoptosis.
"dimerization of Gadd45γ"
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The central region of the GADD45G dimer contains a highly acidic patch that mediates interactions with PCNA, cdc2, and p21.
"a conserved and highly acidic patch on the dimer surface, including the important residues Glu87 and Asp89, is a putative interface for binding proteins related to the cell cycle, DNA repair and apoptosis."