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)

Type beta transforming growth factors represent a family of polypeptides that modulate growth and differentiation. They exert their effect on target cells through interaction with multiple cell surface receptors. Transforming growth factor-beta 1 has a strong inhibitory action on cell division in mink lung CC164 cells, a process that is initiated by immediate induction of junB and phosphorylation of nuclear protein followed by a reduced expression of cdk4. However, its signal transduction pathways are still unresolved. In this study we report a detailed analysis of cell kinetic events following addition of transforming growth factor-beta 1 to mink lung CCL64 cells. We show that transforming growth factor-beta 1 reduces [3H]thymidine incorporation after a delay of 8 hours, which reaches its nadir at 16 hours. The reduced growth rate is maintained for at least 48 hours as shown by flow cytometric analysis of DNA content. Using time-lapse video microscopy it was shown that control cells double on average every 14.4 hours, whereas the transforming growth factor-beta 1-treated cells have a doubling time of on average 20.3 hours. The difference in intermitotic time is a consequence of a prolonged G1 phase (a shift from 7.5 to 13.5 hours on average). However, changes in intermitotic times occur only after cells have undergone division in the presence of transforming growth factor-beta 1 and treated cells finish the ongoing cell cycle exactly like control cells. From these findings we conclude that transforming growth factor-beta 1 may change cell cycle parameters by interfering with cellular events prior to G1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Initiation of growth inhibition by TGF beta 1 is unlikely to occur in G1. 770 98

The role of positive and negative cytokine interactions in G1 cell cycle regulation of haemopoietic cells was analysed by determination of the expression patterns of D-type cyclins and cyclin-dependent kinases (cdks) in SKM-1 myelodysplastic syndrome (MDS) cells incubated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or transforming growth factor-beta 1 (TGF-beta 1). TGF-beta 1 inhibited SKM-1 cell proliferation due to the cell cycle arrest in G1 phase. GM-CSF abrogated the TGF-beta 1-mediated G1 arrest in these cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that TGF-beta 1-mediated G1 arrest correlated with the down-regulation of cdk4, cdk6 and cyclin D2, and that abrogation of TGF-beta 1-mediated G1 arrest by GM-CSF correlated with the constitutive over-expression of cyclin D2 and cdk6 but not cdk4. These results suggest the importance of cyclin D2/cdk6 levels in abrogating G1 arrest in cells exposed to TGF-beta 1, and raise the possibility that the GM-CSF-mediated up-regulatory pathway of signal transduction through cyclin D2/cdk6 differs from the TGF-beta 1-cdk4-mediated pathway in SKM-1 cells. This signal transduction pathway through cyclin D2/cdk6 might play an important role in haemopoietic regulation by the cytokine network.
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PMID:Granulocyte-macrophage colony-stimulating factor abrogates transforming growth factor-beta 1-mediated cell cycle arrest by up-regulating cyclin D2/Cdk6. 933 4

Stress signals activate the SAPK/JNK and p38 MAPK classes of protein kinases, which mediate cellular responses, including steps in apoptosis and the maturation of some cell types. We now show that stress signals initiated by transforming growth factor-beta 1 (TGF-beta 1) induce G(1) arrest through protein stabilization of the CDK inhibitor p21(Cip1). TGF-beta 1 was previously shown to increase p21 protein levels, which in turn mediated G(1) arrest through inactivation of the CDK2-cyclin E complex in HD3 cells (Yan, Z., Kim, G.-Y., Deng, X., and Friedman, E. (2002) J. Biol. Chem. 277, 9870-9879). We now demonstrate that the increase in p21 abundance is caused by a post-transcriptional, SMAD-independent mechanism. TGF-beta1 activated p38 alpha and JNK1, which initiated the phosphorylation of p21. TGF-beta1 treatment increased the half-life of p21 by 3-4-fold. The increase in p21 stability was detected following activation of p38 alpha and JNK1, and treatment of cells with the p38 inhibitor SB203580 prevented this increase in p21 stability. p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro. Peptide mapping demonstrated that both TGF-beta 1 and p38 alpha induced phosphorylation of p21 at Ser(130) in vivo, and mutation of Ser(130) to alanine rendered p21 less stable than wild-type p21. TGF-beta 1 increased the stability of wild-type p21, but not the p21-S130A mutant. These findings demonstrate that SAPKs can mediate cell cycle arrest through post-translational modification of p21.
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PMID:The stress-activated protein kinases p38 alpha and JNK1 stabilize p21(Cip1) by phosphorylation. 1205 28

Currently, the cyclin-dependent kinase inhibitor p21 WAF-1 is considered to be a crucial downstream effector in the p53-specific pathway of negative growth control in mammalian cells. Wild-type p53, but not mutant forms of this protein, transactivate the WAF-1 gene. We show a correlation between growth-inhibition and induction of WAF-1 protein expression following transforming growth factor-beta 1 (TGF-beta 1) treatment of two human tumour cell lines devoid of wild-type p53 protein and in SV40-transformed WI38 fibroblasts. Inversely, TGF-beta 1 treatment of normal WI38 fibroblasts stimulates their growth and represses WAF-1 protein synthesis. As the mink lung epithelial CCL64 cell line is frequently used in TGF-B studies we included it in this study: TGF-beta 1 growth-inhibition is accompanied by induction of WAF-1 synthesis concomitantly with a reduction of cdk2 synthesis and of its histone kinase activity. However in the human tumour line RD, TGF-beta 1 did not affect cdk-2 protein levels but did reduce its histone kinase activity.
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PMID:Differential-effects of transforming growth-factor-Beta-1 on protein-levels of p21 waf and cdk-2 and on cdk-2 kinase-activity in human rd and ccl64 mink lung-cells. 2155 44