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

Expression of the cdc2 gene is induced steeply at the G1-S-phase boundary. The previous analysis of promoter elements that confer inducibility revealed the enhancer at positions -276 to -265. Enhancer activity is suppressed by the upstream sequence that seems to contain the silencer. The silencer element was analyzed by fusing several oligonucleotides covering the silencer region upstream of the enhancer in the cdc2 promoter-luciferase construct. Oligonucleotide IV, which suppressed enhancer activity, was further dissected by the introduction of base substitutions and by forming the DNA-protein complexes with quiescent rat cell extract. The silencer element, AAGTAGTAAAAATA, was finally identified at positions -374 to -360, which resembles the enhancer sequencer but contains extra internal AG residues. Silencer complexes were formed with the quiescent cell extract, whereas the amounts of the complexes decreased with the progression of the cell cycle, and nearly no complexes were formed with the late G1 cell extracts. Conversely, the enhancer complex begins to be formed after late G1. Among the three silencer complexes, the formation of the slowest-migrating complex (complex III) was inhibited by the enhancer sequence, suggesting that a common factor interacts with both the silencer and enhancer. These results suggest that the conversion of complex formation from the silencer to the enhancer site regulates the induction of cdc2 promoter activity at the G1-S-phase boundary.
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PMID:Negative regulation of the rat cdc2 promoter in G1 by the silencer element. 954 92

Transcriptional corepressors of the Groucho/transducin-like Enhancer of split (Gro/TLE) family are involved in a variety of cell differentiation mechanisms in both invertebrates and vertebrates. They become recruited to specific promoter regions by forming complexes with a number of different DNA-binding proteins thereby contributing to the regulation of multiple genes. To understand how the functions of Gro/TLE proteins are regulated, it was asked whether their ability to mediate transcriptional repression might be controlled by cell cycle-dependent phosphorylation events. It is shown here that activation of p34(cdc2) kinase (cdc2) with okadaic acid is correlated with hyperphosphorylation of Gro/TLEs. Moreover, pharmacological inhibition of cdc2 activity results in Gro/TLE dephosphorylation. In agreement with these findings, a purified cdc2-cyclin B complex can directly phosphorylate Gro/TLEs in vitro. Two separate Gro/TLE domains, the CcN and SP regions, contain sequences that are phosphorylated by cdc2. Deletion of these sequences is correlated with loss of Gro/TLE phosphorylation by cdc2 in vitro and okadaic acid-induced Gro/TLE hyperphosphorylation in vivo. In addition, Gro/TLEs are phosphorylated during the G(2)/M phase of the cell cycle, and this is correlated with a decreased nuclear interaction. Finally, the transcription repression ability of Gro/TLEs is enhanced by pharmacological inhibition of cdc2. Taken together, these results demonstrate that Gro/TLE proteins are phosphorylated as a function of the cell cycle and implicate phosphorylation events occurring during mitosis in the negative regulation of Gro/TLE activity.
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PMID:A role for cell cycle-regulated phosphorylation in Groucho-mediated transcriptional repression. 1239 81

Initiation of human myoblast differentiation requires a negative shift (hyperpolarization) of the resting potential of myoblasts that depends on the activation of Kir2.1 potassium channels. These channels are regulated by a tyrosine phosphorylation. Using human primary myoblast culture, we investigated a possible role of various receptor tyrosine kinases in the induction of the differentiation process. We found that Epidermal Growth Factor Receptor (EGFR) is a key regulator of myoblast differentiation. EGFR activity is down-regulated during early human myoblast differentiation, and this event is required for normal differentiation to take place. Furthermore, EGFR silencing in proliferation conditions was able to trigger the differentiation program. This occurs through an increase of Kir2.1 channel activity that, via a rise of store-operated Ca(2+) entry, leads to the expression of myogenic transcription factors and muscle specific proteins (Myogenin, Myocyte Enhancer Factor 2 (MEF2), Myosin Heavy Chain (MyHC)). Finally, blocking myoblast cell cycle in proliferation conditions using a cdk4 inhibitor greatly decreased myoblast proliferation but was not able, on its own, to promote myoblast differentiation. Taken together, these results show that EGFR down-regulation is an early event that is required for the induction of myoblast differentiation.
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PMID:Epidermal growth factor receptor down-regulation triggers human myoblast differentiation. 2396 42