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)

Transforming growth factor beta 1 (TGF beta 1) is a cytokine capable of inhibiting or stimulating cell growth, depending on the nature of the target cell. Inhibition of cell growth by TGF beta 1 is thought to be mediated by TGF beta 1-induced changes in the expression and activity of cell cycle regulatory proteins like cyclin-dependent kinase (cdk) 2 and cdk4. Here we show that adenovirus E1A blocks growth inhibition by TGF beta 1. The activity of cdk2 was strongly inhibited by TGF beta 1 in control cells but not in E1A-expressing cells. Similarly, an early event in TGF beta 1 signaling, junB induction, was significantly reduced in E1A-expressing cells. E1A also interferes with growth stimulation of NRK cells by TGF beta 1, both in monolayer and in soft agar. In these cells, E1A also interferes with junB induction by TGF beta 1. Moreover, E1A abrogates TGF beta 1-induced production of an autocrine-acting platelet-derived growth factor-like activity. These results show that E1A can interfere with TGF beta 1-induced growth-inhibiting as well as growth-promoting signals.
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PMID:Adenovirus E1A antagonizes both negative and positive growth signals elicited by transforming growth factor beta 1. 764 36

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

HIV-1 Rev transactivator is readily phosphorylated at separate regions by protein kinase CK2 and MAP kinase. Protein kinase CK1 cannot replace CK2 as phosphorylating agent and cdc2 only slowly phosphorylates Rev at one of the two sites affected by MAP kinase. Mutational analysis shows that Ser-8 and, to a lesser extent, Ser-5 are phosphorylated by CK2. In contrast, a mutation (R14TV-->EED) which suppresses Rev activity dramatically enhances Rev phosphorylation either in vitro by CK2 or in vivo, suggesting that phosphorylation by CK2 could play a role in Rev down-regulation.
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PMID:Phosphorylation of HIV-1 Rev protein: implication of protein kinase CK2 and pro-directed kinases. 880 71

The activity of the N-terminal activation function AF-1 of RAR alpha1 is abrogated upon mutation of a phosphorylatable serine residue (Ser-77). Recombinant RAR alpha was phosphorylated by a variety of proline-directed protein kinases in vitro. However, only the coexpression of cdk7 stimulated Ser-77 phosphorylation in vivo and enhanced transactivation by RAR alpha, but not by a S77A RAR mutant. Both free CAK (cdk7, cyclin H, MAT1) and the CAK-containing general transcription factor TFIIH phosphorylated Ser-77 in vitro. Furthermore RAR alpha bound free CAK and purified TFIIH in vitro, and RAR alpha-TFIIH complexes could be isolated from HeLa nuclear extracts. These findings represent the first example of activation of a transactivator through binding to and phosphorylation by a general transcription factor.
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PMID:Stimulation of RAR alpha activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by CDK7. 923 Mar 6

We demonstrate in this paper that CDK4 which is a G1 phase specific cell cycle regulator and catalytic subunit of D-type cyclins has oncogenic activity similar to D-type cyclins themselves and is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts. Surprisingly, using two different mutants we show that CDK4's ability to bind to p16INK4a and not its kinase activity is important for its transforming potential. In addition, p16INK4a but not a mutant form that is found in human tumours can completely abrogate focus formation by CDK4 suggesting that CDK4 can malignantly transform cells by sequestering p16INK4a or other CKIs. We demonstrate that both cyclin D1 and CDK4 functionally depend on active Myc to exert their potential as oncogenes and vice versa that the transforming ability of Myc requires functional cyclin D/CDK complexes. Moreover, we find that p16INK4a and the Rb related protein p107 which releases Myc after phosphorylation by cyclin D1/CDK4 efficiently block Myc's activity as a transcriptional transactivator and as an oncogene. We conclude that both p16INK4a and cyclin D/CDK4 complexes are upstream regulators of Myc and directly govern Myc function in transcriptional transactivation and transformation via the pocket protein p107.
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PMID:Mutual requirement of CDK4 and Myc in malignant transformation: evidence for cyclin D1/CDK4 and p16INK4A as upstream regulators of Myc. 924 53

Leukemia inhibitory factor (LIF) affects the growth of carcinoma cells, and we thus analyzed its underlying mechanisms. Carcinoma cells constitutively express LIF mRNA, and 23 lines (92.0%) and all (100%) of 25 lines express LIF receptor mRNAs of LIFRbeta and gp130, respectively. Exogenous addition of LIF promoted significant cell proliferation in 4 lines (MCF-7, ZR-75-1, Hs-700T and Panc-1) and suppressed cell growth in 3 lines (AZ-521, GBK-1 and HT-29). LIF significantly induced an immediate early response of genes c-fos and junB 3 hr after stimulation, but not of c-jun during the process of proliferation of MCF-7 and Hs-700T cells, with maximum levels at 30-60 min. The cell-cycle-related gene cyclin E was also induced in MCF-7 and Hs-700T cells, whereas cyclinA, cdk2, c-myc, c-myb and p53 mRNAs were not induced. On the other hand, LIF inhibited growth and increased the rate of cell death of AZ-521 and GBK-1 cells. LIF increased the number of TUNEL-positive cells in AZ-521 cells and DNA fragmentation in AZ-521 and GBK-1 cells. LIF induced apoptosis related genes c-myc and ICE during suppression of cell growth, but p53, p21, c-fos, cyclin A and cyclin E were not induced. Our results suggest that LIF is linked to cell proliferation and apoptosis in some human carcinoma cell lines. It is considered that this is related to differences in signal transduction and induction of oncogenes.
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PMID:Leukemia inhibitory factor induces apoptosis and proliferation of human carcinoma cells through different oncogene pathways. 925 11

The Tax proteins of the oncovirinae viruses are phosphorylated transcriptional activators that exhibit oncogenic potential. The role of phosphorylation in their functional activities remains unknown. As a model for the Human T-cell leukemia virus type I (HTLV-I), Bovine Leukemia Virus (BLV) permits the characterization of viral replication and leukemogenesis in vivo. Here, we show that the BLV Tax protein is phosphorylated on serine residues 106 and 293 both in insect and in mammalian cells. These sites can also be efficiently phosphorylated by the cdc2 and MAP kinases in vitro. Mutation of these residues does not affect the capacity of the Tax protein to function as a transactivator. Indeed, the Tax proteins mutated at one or both serines increase LTR-directed viral transcription at levels similar to those obtained with wild-type Tax in cell culture. Moreover, inhibition of Tax phosphorylation by W7, a calmodulin antagonist, does not alter its transactivation activity. Thus, phosphorylation on serines 106 and 293 is not required for transactivation by Tax. However, simultaneous substitution of both serines into alanine residues destroys the capacity of Tax to cooperate with the Ha-ras oncogene to transform primary rat embryo fibroblasts and induce tumors in nude mice. When the serines were replaced with aspartic acid residues, the oncogenic potential of Tax was maintained indicating that the negative charge rather than the phosphate group itself was required for Tax oncogenicity. Finally, to assess the role of the serine residues in vivo, recombinant viruses which express the Tax mutants were constructed and injected into sheep. It appeared that the mutated proviruses replicate at levels similar to the wild-type virus in vivo. We conclude that Tax phosphorylation is dispensable for transactivation and viral replication in vivo but is required for its oncogenic potential in vitro.
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PMID:Phosphorylation of bovine leukemia virus Tax protein is required for in vitro transformation but not for transactivation. 961 25

The CDK inhibitor p21WAF1/CIP1 is a negative regulator of the cell cycle, and its expression is induced during terminal differentiation in vitro and in vivo. Expression of p21 is controlled at the transcriptional level by both p53-dependent and -independent mechanisms. Our previous studies established that p21 is expressed in the Caco-2 adenocarcinoma cell line, and its expression is induced by a p53-independent mechanism during differentiation of these cells. Here we have found that transcription of p21 in Caco-2 cells is controlled primarily by the transcription factors Sp1 and Sp3 through two Sp1 binding sites, Sp1-1 and Sp1-2, located between -119 and -114 bp and between -109 and -104 bp of the p21 promoter, respectively. Sp1 and Sp3 binding to the p21 promoter increased during Caco-2 cell differentiation, while the absolute level of Sp1 did not change and the absolute level of Sp3 increased approximately twofold. Transfection experiments in the SL2 Drosophila cell line that lacks endogenous Sp3 activity demonstrated that Sp1 transactivates the p21 promoter primarily through the Sp1-2 site, while Sp3 acts through the Sp1-1 site. In these cells Sp3 is a stronger transactivator of the p21 promoter than Sp1. Our data suggest that induction of p21 transcription during Caco-2 differentiation is modulated by Sp1/Sp3 interactions with the p21 promoter.
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PMID:Sp1 and Sp3 activate p21 (WAF1/CIP1) gene transcription in the Caco-2 colon adenocarcinoma cell line. 1106 55

We have explored the effects of the conditional MYC-estrogen receptor fusion protein, MYC-ERTM, in human mortal fibroblasts, WI38, on cell-cycle entry, apoptosis and gene expression. The results indicate that activation of MYC-ERTM in WI38 cells is sufficient to cause S phase entry of quiescent cells, which is preceded by phosphorylation of Rb and activation of the Cdk2-associated kinase. We also analysed the MYC protein variant, MYC-S, which lacks part of the transcriptional activation domain but includes the conserved MYC box II and 26 amino acids N-terminal to it. MYC-S was previously shown to promote proliferation and apoptosis of immortalized rodent cell lines. The results indicate that MYC-S has undetectable activity as an inducer of S phase or apoptosis of quiescent WI38 cells. However, Myc-S stimulates proliferation of WI38 cells in the presence of 10% fetal calf serum. Surprisingly, we found that MYC-S, previously considered solely a repressor of specific reporter genes, is instead a weak transactivator of endogenous target genes both in mortal and immortalized cells. In addition, MYC-S exhibit a weak repressor activity upon an endogenous target gene only in immortalized cells. MYC-S transcriptional properties suggest that MYC box II and the adjacent N-terminal amino acids, while not sufficient for full repression function, participate in transactivation of endogenous target genes.
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PMID:Differential activity of conditional MYC and its variant MYC-S in human mortal fibroblasts. 1106 56

Earlier reports from this laboratory have shown that the promiscuous transactivator infected-cell protein 0 (ICP0) binds and stabilizes cyclin D3, that the binding site maps to aspartic acid 199 (D199), and that replacement of D199 with alanine abolishes binding and reduces the capacity of the mutant virus to replicate in quiescent cells or to cause mortality in mice infected by a peripheral site. The objective of this report was to investigate the role of cyclin D3 in the biology of ICP0. We report the following results. (i) Wild-type ICP0 activates cyclin D-dependent kinase 4 (cdk4) and stabilizes cyclin D1 although ICP0 does not interact with this cyclin. (ii) The D199A mutant virus (R7914) does not activate cdk4 or stabilize cyclin D1, and neither the wild-type nor the mutant virus activates cdk2. (iii) Early in infection of human embryonic lung (HEL) fibroblasts both wild-type and D199A mutant ICP0s colocalize with PML, and in these cells the ND10 nuclear structures are dispersed. Whereas wild-type ICP0 is transported to the cytoplasm between 3 and 9 h. after infection, ICPO containing the D199A substitution remains quantitatively in the nucleus. (iv) To examine the interaction of ICP0 with cyclin D3, we used a previously described mutant carrying a wild-type ICP0 but expressing cyclin D3 (R7801) and in addition constructed a virus (R7916) that was identical except that it carried the D199A-substituted ICP0. Early in infection with R7801, ICP0 colocalized with cyclin D3 in structures similar to those containing PML. At 3 h after infection, ICP0 was translocated to the cytoplasm whereas cyclin D3 remained in the nucleus. The translocation of ICP0 to the cytoplasm was accelerated in cells expressing cyclin D3 compared with that of ICP0 expressed by wild-type virus. In contrast, ICP0 carrying the D199A substitution remained in the nucleus and did not colocalize with cyclin D3. These studies suggest the following conclusions. (i) ICP0 brings to the vicinity of ND10 cyclin D3 and, in consequence, an activated cdk4. The metabolic events occurring at or near that structure and involving cyclin D3 cause the translocation of ICP0 to the cytoplasm. (ii) In the absence of the cyclin D3 binding site in ICP0, cyclin D3 is not brought to ND10, cyclin D is not stabilized, and the function responsible for the translocation of ICP0 is not expressed, and in quiescent HEL fibroblasts the yields of virus are reduced.
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PMID:Role of cyclin D3 in the biology of herpes simplex virus 1 ICPO. 1116 Jun 88


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