Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of cell growth by type beta transforming growth factor (TGF-beta) occurs in mid-G1 and is associated with decreased G1 cyclin-dependent kinase activity and maintenance of the retinoblastoma tumor suppressor protein Rb in an underphosphorylated, growth-suppressive state. A variety of recent experiments suggest that a functional target of Rb is the E2F transcription factor. In addition, the growth-suppressive effects of TGF-beta can be overcome by expression of viral oncogene products that dissociate E2F from Rb and Rb-related polypeptides. These results suggest the possibility that control of E2F may be a downstream event of TGF-beta action. Consistent with that possibility is the observation that E2F1 RNA levels are drastically reduced in TGF-beta-treated cells. We have also used a recombinant adenovirus containing the human E2F1 gene to overexpress the E2F1 product in mink lung epithelial cells that were growth arrested with TGF-beta. We find that overexpression of E2F1 can overcome the TGF-beta-mediated effect as measured by the activation of cellular DNA synthesis. These results suggest that a likely downstream target for the cyclin-dependent kinases, which are controlled by TGF-beta, is the activation of E2F.
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PMID:Expression of the E2F1 transcription factor overcomes type beta transforming growth factor-mediated growth suppression. 783 15

Both positive and negative signals govern the progression of cells from G1 into S phase, and a variety of data implicate the E2F transcription factor as a target for the action of one class of negative regulators, the Rb family of growth suppressors. We now find that the E2F1 gene, which encodes one of the components of E2F activity, is subject to autoregulatory control during progression from G0 to S phase and that this primarily reflects a negative control in G0 and early G1, a time when the majority of E2F activity exits as a complex with Rb family members. In addition, we find that deregulated expression of G1 cyclins in quiescent cells stimulates the E2F1 promoter and that this is augmented by coexpression of cyclin-dependent kinases in an E2F-dependent manner. We conclude that the E2F1 gene is a downstream target for G1 cyclin-dependent kinase activity, most likely as a consequence of phosphorylation of Rb family members, and that the autoregulation of E2F1 transcription may provide a sensitive switch for regulating the accumulation of E2F activity during the transition from G1 to S phase.
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PMID:Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. 795 36

Alterations of various components of the cell cycle regulatory machinery that controls the progression of cells from a quiescent to a growing state contribute to the development of many human cancers. Such alterations include the deregulated expression of G1 cyclins, the loss of function of activities such as those of protein p16INK4a that control G1 cyclin-dependent kinase activity, and the loss of function of the retinoblastoma protein (RB), which is normally regulated by the G1 cyclin-dependent kinases. Various studies have revealed an inverse relationship in the expression of p16INK4a protein and the presence of functional RB in many cell lines. In this study we show that p16INK4a is expressed in cervical cancer cell lines in which the RB gene, Rb, is not functional, either as a consequence of Rb mutation or expression of the human papillomavirus E7 protein. We also demonstrate that p16INK4a levels are increased in primary cells in which RB has been inactivated by DNA tumor virus proteins. Given the role of RB in controlling E2F transcription factor activity, we investigated the role of E2F in controlling p16INK4a expression. We found that E2F1 overexpression leads to an inhibition of cyclin D1-dependent kinase activity and induces the expression of a p16-related transcript. We conclude that the accumulation of G1 cyclin-dependent kinase activity during normal G1 progression leads to E2F accumulation through the inactivation of RB, and that this then leads to the induction of cyclin kinase inhibitor activity and a shutdown of G1 kinase activity.
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PMID:Inhibition of cyclin D-CDK4/CDK6 activity is associated with an E2F-mediated induction of cyclin kinase inhibitor activity. 863 69

Previous studies have demonstrated cell cycle-dependent specificities in the interactions of E2F proteins with Rb family members. We now show that the formation of an E2F-p130 complex is unique to cells in a quiescent, G0 state. The E2F-p130 complex does not reform when cells reenter a proliferative state and cycle through G1. The presence of an E2F-p130 complex in quiescent cells coincides with the E2F-mediated repression of transcription of the E2F1 gene, and we show that the E2F sites in the E2F1 promoter are important as cells enter quiescence but play no apparent role in cycling cells. In addition, the decay of the E2F-p130 complex as cells reenter the cell cycle requires the action of G1 cyclin-dependent kinase activity. We conclude that the accumulation of the E2F-p130 complex in quiescent cells provides a negative control of certain key target genes and defines a functional distinction between these G0 cells and cells that exist transiently in G1.
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PMID:The accumulation of an E2F-p130 transcriptional repressor distinguishes a G0 cell state from a G1 cell state. 894 52

The initiation of DNA replication in Saccharomyces cerevisiae requires the action of a multisubunit complex of six proteins known as the origin recognition complex (ORC). The identification of higher eukaryotic homologs of several ORC components suggests a universal role for this complex in DNA replication. We now demonstrate that the expression of one of these homologs is regulated by cell proliferation. Expression of the human Orc1 gene (HsOrc1) is low in quiescent cells, and it is then dramatically induced upon stimulation of cell growth. In contrast, expression of the HsOrc2 gene does not appear to be similarly regulated. We have isolated the promoter that regulates HsOrc1 transcription, and we show that the promoter confers cell growth-dependent expression. We also demonstrate that the cell growth control is largely the consequence of E2F-dependent negative transcription control in quiescent cells. Activation of HsOrc1 transcription following growth stimulation requires G1 cyclin-dependent kinase activity, and forced E2F1 expression can bypass this requirement. These results thus provide a direct link between the initiation of DNA replication and the cell growth regulatory pathway involving G1 cyclin-dependent kinases, the Rb tumor suppressor, and E2F.
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PMID:Expression of the HsOrc1 gene, a human ORC1 homolog, is regulated by cell proliferation via the E2F transcription factor. 894 53

Understanding the growth constraints imposed on normal human melanocytes may help to elucidate the processes conferring growth advantage to melanoma cells. Several synergistic growth factors have been identified for normal human melanocytes. They include fibroblast growth factors (FGF), hepatocyte growth factor/scatter factor, mast/stem cell growth factor, and the neuropeptides endothelin-1, 2 and 3 (ET-1, ET-2, ET-3). From this group of peptides, only basic FGF (bFGF/FGF2) appears, so far, to play a role in autonomous growth of melanoma cells. Aberrant expression of FGF2 is due to activation of an otherwise repressed gene by a mechanism that may involve the transcriptional activity of wild-type p53. The growth factors and activated receptors aberrantly expressed in melanoma cells act in concert with molecules that control cell cycle progression. These proteins bind to, and regulate cyclin-dependent kinase (CDK), such as CDK4, responsible for phosphorylation of retinoblastoma (RB) and dissociation of RB-E2F1 inhibitory complexes, thereby allowing progression through the cell cycle. Constitutive CDK4 activity in melanomas may be the results of inactivation of the negative regulators known as CDK inhibitor p16INK4, and/or p21; and/or overexpression of cyclin D, the positive CDK4 regulator. This complex set of changes in melanoma cells can lift growth constraints by inducing unregulated expression of genes promoting transition from GI to S phase of the cell cycle.
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PMID:Growth factors and melanomas. 897 May 86

In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-based thymidylate synthase inhibitor, resulted in DNA fragmentation. In this study, we have demonstrated the dose- and time-dependent induction of DNA fragmentation accompanied by elevation of p53 and WAF1 protein expression by ZD1694. WAF1 mRNA showed a time-dependent increase, whereas p53 mRNA was not found to be significantly overexpressed. The initial increase in WAF1 mRNA was detected at 4 hr, but increased WAF1 protein expression was detected 8-24 hr after a 2-hr exposure. The amount of total and hypophosphorylated pRb seems to be rising greatly after ZD1694 exposure. The effects of ZD1694 on the expression of E2F1 and formation of the E2F1-Rb complex were investigated after a 2-hr drug exposure (IC90). The results showed a time-dependent decrease in E2F1 mRNA and protein expression; an increase in the abundance of the E2F-Rb complex could be demonstrated beginning 4 hr after drug exposure by a gel shift assay. Kinetic analysis showed increased availability of hypophosphorylated pRb for inhibition of E2F, which could indirectly result from WAF1-induced inhibition cyclin-dependent kinase activity. Whereas thymidylate synthase inhibition by ZD1694 was rapid in onset and maintained for at least 24 hr after drug treatment, drug-induced cellular growth inhibition was significant 24 hr after drug exposure. The increased abundance of hypophosphorylated pRb and binding to transcription factor E2F-1 is consistent with ZD1694-induced cell growth inhibition in HCT-8 cells. Therefore, the observed effect on downstream events after effective inhibition of thymidylate synthase may offer the critical determinants of response to ZD1694.
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PMID:p53 and WAF1 are induced and Rb protein is hypophosphorylated during cell growth inhibition by the thymidylate synthase inhibitor ZD1694 (Tomudex). 910 28

The product of the c-mos proto-oncogene is a protein kinase that is normally expressed in germ cells and functions during oocyte maturation. It has been shown, however, that inappropriate expression of either the viral or cellular mos gene can induce neoplastic progression in somatic cells. Furthermore, v-mos-transformed NIH3T3 cells will undergo arrest of proliferation in early G1 upon serum withdrawal but are unable to appropriately down-regulate cell cycle regulatory proteins, such as cyclin and cdc2 proteins, that normally are down-regulated in quiescent, untransformed NIH3T3 cells. Since the levels of these proteins are partially transcriptionally controlled, we investigated whether there were alterations in the expression of E2F and AP-1 transcription factor complexes. Indeed, the putative G0/G1-specific p130-E2F complex that is normally observed during low serum-induced cell cycle arrest in NIH3T3 cells is not present in serum starved v-mos-transformed cells. Instead, G1-phase arrested v-mos-transformed cells stably express two E2F protein complexes that are normally observed only during S-phase in untransformed cells. The elevation of these complexes in arrested v-mos-transformed cells may be the cause of the transcriptional activation of the E2F-regulated genes cdc2, DHFR, cyclin A, and E2F1 seen in serum starved v-mos-transformed cells. In addition, there are high levels of AP-1 DNA binding activity in serum starved v-mos-transformed cells compared to very low amounts in nontransformed cells. This altered regulation of transcription factor complexes and cell cycle control proteins upon serum withdrawal may provide a mechanism for the uncontrolled cell growth associated with neoplastic transformation induced by certain proto-oncogenes.
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PMID:Deregulation of specific E2F complexes by the v-mos oncogene. 922 66

One of the most studied and best-understood examples of second messenger-regulated gene transcription involves the activation of genes by the cyclic AMP pathway: stimulation of several hormone, growth factor, and neurotransmitter receptors activates adenylyl cyclase, generating cyclic AMP that, by binding to the regulatory subunit of protein kinase A (PKA), dissociates the PKA catalytic subunit. The free catalytic subunit is transported to the nucleus where it phosphorylates and consequently activates the transcription factor CREB. This phosphorylation of CREB allows interaction with the co-activator CBP, which binds to components of the basal transcriptional machinery. CBP and its homologue p300 are targets for several viral-transforming proteins, implying that these co-activators have a more extensive role in cellular function. Indeed, recent studies have demonstrated that multiple transcription factors bind to CBP, including c-jun, c-myb, MyoD, E2F1, YY1, and members of the steroid hormone receptor superfamily, although it is not yet clear which of these transcription factors depend upon CBP for function. Determining exactly which transcriptional pathways require CBP in vivo and which genes are activated by CBP will provide an important clue in developmental regulation and cell cycle control, since mutations in the human CBP gene have been found to cause developmental abnormalities and a predisposition for some types of cancer. In this review, we will discuss the mechanisms involved in the PKA-dependent activation of CREB and describe how the co-activator CBP and its homologue are involved in this process. In addition, we will outline the various transcription factor pathways that CBP has been proposed to activate. Finally, we will discuss the possible role of CBP in cellular transformation and differentiation.
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PMID:The multifunctional role of the co-activator CBP in transcriptional regulation. 923 49

To study the molecular basis for the clinical phenotype of incomplete penetrance of familial retinoblastoma, we have examined the functional properties of three RB mutations identified in the germ line of five different families with low penetrance. RB mutants isolated from common adult cancers and from classic familial retinoblastoma (designated as classic RB mutations) are unstable and generally do not localize to the nucleus, do not undergo cyclin-dependent kinase (cdk)-mediated hyperphosphorylation, show absent protein "pocket" binding activity, and do not suppress colony growth of RB(-) cells. In contrast, two low-penetrant alleles (661W and "deletion of codon 480") retained the ability to localize to the nucleus, showed normal cdk-mediated hyperphosphorylation in vivo, exhibited a binding pattern to simian virus 40 large T antigen using a quantitative yeast two-hybrid assay that was intermediate between classic mutants (null) and wild-type RB, and had absent E2F1 binding in vitro. A third, low-penetrant allele, "deletion of RB exon 4," showed minimal hyperphosphorylation in vivo but demonstrated detectable E2F1 binding in vitro. In addition, each low-penetrant RB mutant retained the ability to suppress colony growth of RB(-) tumor cells. These findings suggest two categories of mutant, low-penetrant RB alleles. Class 1 alleles correspond to promoter mutations, which are believed to result in reduced or deregulated levels of wild-type RB protein, whereas class 2 alleles result in mutant proteins that retain partial activity. Characterization of the different subtypes of class 2 low-penetrant genes may help to define more precisely functional domains within the RB product required for tumor suppression.
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PMID:Incomplete penetrance of familial retinoblastoma linked to germ-line mutations that result in partial loss of RB function. 934 58


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