Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gadd45a (Gadd45), Gadd45b (MyD118), and Gadd45g (CR6) constitute a family of evolutionarily conserved, small, acidic, nuclear proteins, which have been implicated in terminal differentiation, growth suppression, and apoptosis. How Gadd45 proteins function in negative growth control is not fully understood. Recent evidence has implicated Gadd45a in inhibition of cdc2/cyclinB1 kinase and in G2/M cell cycle arrest. Yet, whether Gadd45b and/or Gadd45g function as inhibitors of cdc2/cyclinB1 kinase and/or play a role in G2/M cell cycle arrest has not been fully established. In this work, we show that Gadd45b and Gadd45g specifically interact with the Cdk1/CyclinB1 complex, but not with other Cdk/Cyclin complexes, in vitro and in vivo. Data also has been obtained that Gadd45b and Gadd45g, as well as GADD45a, interact with both Cdk1 and cyclinB1, resulting in inhibition of the kinase activity of the Cdk1/cyclinB1 complex. Inhibition of Cdk1/cyclinB1 kinase activity by Gadd45b and Gadd45a was found to involve disruption of the complex, whereas Gadd45g did not disrupt the complex. Moreover, using RKO lung carcinoma cell lines, which express antisense Gadd45 RNA, data has been obtained, which indicates that all three Gadd45 proteins are likely to cooperate in activation of S and G2/M checkpoints following exposure of cells to UV irradiation.
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PMID:GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. 1212 78

The Gadd45 family of proteins includes Gadd45alpha, MyD118/Gadd45beta, and CR6/OIG37/Gadd45gamma. These proteins play important roles in maintaining genomic stability and in regulating the cell cycle. This study reports the cloning of a novel protein called CR6-interacting factor 1 (CRIF1) which interacts with Gadd45alpha, MyD118/Gadd45beta, and CR6/OIG37/Gadd45gamma. 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. CRIF1 mRNA is highly expressed in the thyroid gland, heart, lymph nodes, trachea, and adrenal tissues. CRIF1 localizes exclusively to the nucleus and colocalizes with Gadd45gamma. 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. Overexpression of CRIF1 increases the percentage of cells in G1, decreases the percentage of cells in S phase, and suppresses growth in NIH3T3 cells. The down-regulation of endogenous CRIF1 by the transfection of the small interfering RNA duplexes resulted in the inactivation of Rb by phosphorylation and decreased the G1 phase cell populations. Expression of CRIF1 is barely detectable in adrenal adenoma and papillary thyroid cancer and much lower than in adjacent normal tissue. The results presented here suggest that CRIF1 is a novel nuclear protein that interacts with Gadd45 and may play a role in negative regulation of cell cycle progression and cell growth.
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PMID:CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle. 1271 9

Gadd45g/CR6, Gadd45b/MyD118, and Gadd45a/Gadd45 are members of a gene family that displays distinct patterns of gene expression in response to stimuli that induce differentiation, growth arrest, and/or apoptosis. All three of these highly conserved proteins interact with a number of critical cell cycle and cell survival regulatory proteins such as PCNA, p21(WAF1/CIP1), CDK1 (cdc2-p34), and MTK1/MEKK4, and have been reported to influence the activity of the p38 and JNK kinases. Species-blot analysis showed that Gadd45g is an evolutionarily conserved gene and sequence analysis showed that Gadd45g has a gene structure conserved with that of other members of its gene family. A comparison of the putative transcription factor binding sites found in the sequences of the gene family members suggests, that like Gadd45b, NF-kappaB and STATs may be responsible for the differences in regulation of expression observed between Gadd45g and Gadd45a. Analysis of the Gadd45b/MyD118 promoter shows that there are three different enhanceosome-like regions that may allow cell-type specific responses to TGF-beta1 by the Gadd45b/MyD118 promoter. Fluorescent in situ hybridization (FISH) confirmed the localization of the Gadd45g gene to mouse chromosome band 13A5-B, which has been reported to contain a quantitative trait locus that regulates body weight in mice. This suggests that alleles of the Gadd45g gene may function in the regulation of body weight, in addition to its currently recognized roles in differentiation and stress responses.
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PMID:Comparative analysis of the genetic structure and chromosomal mapping of the murine Gadd45g/CR6 gene. 1293 4

The mechanisms of tumorigenesis of the human pituitary have been elucidated to a limited extent. Classically, pituitary tumor formation was shown to be induced by thyroidectomy and estrogen administration. Molecular biological and immunohistochemical studies have revealed several aspects of pituitary tumorigenesis. Translineage cell differentiation has been shown to be induced by the aberrant expression of transcription factors and co-factors, such as Pit-1, Prop-1, and estrogen receptor. Defects or overexpression of cell cycle regulators, such as CDK inhibitors, PTTG, and GADD45gamma, result in the abnormal proliferation of pituitary cells. Recently, epigenetic regulation has been suggested to be related to pituitary tumor formation. This article presents a review and update of recent progress in studies of the development and differentiation of pituitary tumors.
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PMID:Recent progress in studies of pituitary tumor pathogenesis. 1631 8