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)

The mechanism of cell cycle withdrawal during terminal differentiation is poorly understood. We report here that the cyclin-dependent kinase (CDK) inhibitor p21Cip1/WAF1 is induced at early times of both keratinocyte and myoblast differentiation. p21Cip1/WAF1 induction is accompanied by a drastic inhibition of total Cdk2, as well as p21Cip1/WAF1-associated CDK kinase activities. p21Cip1/WAF1 has been implicated in p53-mediated G1 arrest and apoptosis. In keratinocyte differentiation, Cip1/WAF1 induction is observed even in cells derived from p53-null mice. Similarly, keratinocyte differentiation is associated with induction of Cip1/WAF1 promoter activity in both wild-type and p53-negative keratinocytes. Induction of the Cip1/WAF1 promoter upon differentiation is abolished by expression of an adenovirus E1A oncoprotein (d1922/947), which is unable to bind p105-Rb, p107, or cyclin A but which still binds the nuclear phosphoprotein p300. Overexpression of p300 can suppress the E1A effect, independent of its direct binding to E1A. Thus, terminal differentiation-induced growth arrest in both keratinocyte and myoblast systems is associated with induction of Cip1/WAF1 expression. During keratinocyte differentiation, Cip1/WAF1 induction does not require p53 but depends on the transcriptional modulator p300.
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PMID:Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation. 777 29

The 265K nuclear protein CBP was initially identified as a co-activator for the protein kinase A (PKA)-phosphorylated form of the transcription factor CREB. The domains in CBP that are involved in CREB binding and transcriptional activation are highly related to the adenoviral E1A-associated cellular protein p300 (refs 2, 3), and to two hypothetical proteins from Caenorhabditis elegans, R10E11.1 and K03H1.10 (refs 4 and 5, respectively), whose functions are unknown. Here, we show that CBP and p300 have similar binding affinity for the PKA-phosphorylated form of CREB, and that p300 can substitute for CBP in potentiating CREB-activated gene expression. We find that E1A binds to CBP through a domain conserved with p300 and represses the CREB-dependent co-activator functions of both CBP and p300. Our results indicate that the gene repression and cell immortalization functions associated with E1A involve the inactivation of a family of related proteins that normally participate in second-messenger-regulated gene expression.
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PMID:Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP. 787 Jan 79

Transcriptional activation of the c-fos gene in mouse S49 cells by the adenovirus 243-amino-acid E1A protein depends on domains of E1A that are also required for transformation and that bind the cellular protein p300. Activation additionally depends on stimulation of endogenous cyclic AMP (cAMP)-dependent protein kinase by analogs or inducers of cAMP. Transient transfection assays were used to analyze the c-fos promoter for sequences that confer responsiveness to E1A. Linker substitution and point mutants revealed that transcriptional activation by E1A depended on a cAMP response element (CRE) located at -67 relative to the start site of transcription and a neighboring binding site for transcription factor YY1 located at -54. A 22-bp sequence containing the -67 CRE and the -54 YY1 site was sufficient to confer responsiveness to a minimal E1B promoter and was termed the c-fos E1A response element (ERE). Function of the c-fos ERE depended on both the CRE and the YY1 site, since mutation of either site resulted in a loss of responsiveness to E1A. These results imply a specific functional interaction between CRE-binding proteins, transcription factor YY1, and E1A in the regulation of the c-fos gene.
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PMID:Identification of a novel E1A response element in the mouse c-fos promoter. 788 79

Several signaling molecules have been identified which act as inhibitors of epithelial cell growth. The mechanisms for this negative growth regulation are still poorly understood. In the case of TGF-beta, inhibition of keratinocyte cell growth can be totally prevented by transformation with an intact early region 1a (E1a) oncogene. We show here that E1a-transformed keratinocytes become also partially resistant to growth inhibition by elevated 3',5'-cyclic adenosine monophosphate (cAMP) levels, as induced by treatment with forskolin, dibutyryl-cAMP, 8Br-cAMP, or 8Cl-cAMP. Resistance to cAMP is due to interference of E1a with signaling pathways downstream of protein kinase A (PKA) activation, as intracellular cAMP levels and PKA activity were found to be similar in control and E1a-transformed cells. Induction of c-fos expression by 8Br-cAMP occurs at the same time in both cell lines. Interestingly however, this effect is maintained longer in the case of E1a-transformed cells compared to the control. A truncated E1a mutant which is still able to bind to the p105-Rb gene product, p107, and p60/cyclin A, induces cAMP resistance at levels which are only slightly lower than those induced by an intact E1a oncogene. In contrast, an E1a mutant which binds only to a p300 cellular protein and induces a substantial level of TGF-beta resistance fails to induce cAMP resistance. Thus, E1a transformation counteracts the growth-inhibitory effects of cAMP as well as TGF-beta, but to a different degree and through an only partially overlapping mechanism.
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PMID:Counteracting effects of E1a transformation on cAMP growth inhibition. 839 67

The transcription factor CREB (cAMP responsive element binding protein) is activated by protein kinase A (PKA) phosphorylation of a single serine residue. To investigate possible mechanisms of CREB regulation by phosphorylation, we initiated a structural and biophysical characterization of the full-length, wild-type CREB protein, an altered CREB protein (CREB/SER) in which the three cysteine residues in the DNA-binding domain were replaced with serine residues and a truncated protein (ACT265) which encompasses the entire activation domain of CREB. Circular dichroism (CD) reveals that CREB and CREB/SER have identical secondary structures and contain approximately 20% alpha-helix, 9% beta-strand, 34% beta-turn, and 37% random coil structures. PKA phosphorylation does not alter the CD spectra, and therefore the secondary structure, of CREB or of CREB bound to DNA. Protease cleavage patterns indicate that PKA phosphorylation does not induce a global conformational change in CREB. Furthermore, PKA phosphorylation does not change the DNA binding affinity of CREB for either canonical or non-canonical CRE sequences as measured by a fluorescence anisotropy DNA binding assay. Since PKA phosphorylation of CREB results in its specific binding to the transcriptional co-activators CREB-binding protein and p300, we suggest that the PKA activation of CREB occurs by the production of specific, complementary interactions with these proteins, rather than through the previously proposed mechanisms of a phosphorylation-dependent conformational change or increased DNA binding affinity.
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PMID:Analysis of the structural properties of cAMP-responsive element-binding protein (CREB) and phosphorylated CREB. 866 19

CREB-binding protein (CBP) functions as a coactivator molecule for a number of transcription factors including CREB, c-Fos, c-Jun, c-Myb, and several nuclear receptors. Although binding sites for these factors within CBP have been identified, the regions of CBP responsible for transcriptional activation are unknown. In this report, we show that the N-terminal half of CBP is sufficient for activation of CREB-mediated transcription and that this region contains a strong transcriptional activation domain (TAD). Both deletion of this TAD or sequestering of factors that the TAD binds using a squelching assay were found to greatly decrease the ability of CBP to activate CREB-mediated transcription. In vivo studies by others have shown that p300/CBP associates with TBP; using an in vitro approach, we show the N-terminal TAD binds TBP. We also examined the ability of the C terminus of CBP to activate transcription using GAL-CBP chimeras. With this approach, we identified two C-terminal TADs located adjacent to the c-Fos binding site. In previous studies, cAMP-dependent protein kinase A (PKA) increased the transcriptional activity of a GAL full-length CBP chimera in F9 cells, and of the C terminus in PC-12 cells. Here, we demonstrate that PKA also increased the ability of the N-terminal TADs of CBP to activate transcription in PC-12 but not F9 or COS-7 cells, suggesting that this PKA-responsiveness is cell type-specific.
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PMID:CREB-binding protein activates transcription through multiple domains. 891 Apr 28

The nuclear factor kappaB (NF-kappaB) transcription factor is responsive to specific cytokines and stress and is often activated in association with cell damage and growth arrest in eukaryotes. NF-kappaB is a heterodimeric protein, typically composed of 50- and 65-kilodalton subunits of the Rel family, of which RelA(p65) stimulates transcription of diverse genes. Specific cyclin-dependent kinases (CDKs) were found to regulate transcriptional activation by NF-kappaB through interactions with the coactivator p300. The transcriptional activation domain of RelA(p65) interacted with an amino-terminal region of p300 distinct from a carboxyl-terminal region of p300 required for binding to the cyclin E-Cdk2 complex. The CDK inhibitor p21 or a dominant negative Cdk2, which inhibited p300-associated cyclin E-Cdk2 activity, stimulated kappaB-dependent gene expression, which was also enhanced by expression of p300 in the presence of p21. The interaction of NF-kappaB and CDKs through the p300 and CBP coactivators provides a mechanism for the coordination of transcriptional activation with cell cycle progression.
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PMID:Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. 899 95

The adenovirus early gene product E1A is a potent stimulator of cellular proliferation, which when overexpressed can overcome the growth-inhibitory effects of the polypeptide hormone transforming growth factor beta (TGF-beta). The ability of TGF-beta to arrest cell growth in G1 correlates with the transcriptional induction of the cyclin-dependent kinase inhibitors, p15/INK4B and p21/WAF1/Cip1; an inhibition of the G1 cyclin-Cdk complexes; and a maintenance of the retinoblastoma susceptibility gene product, Rb, in a hypophosphorylated state. The ability of E1A to overcome TGF-beta-mediated growth inhibition derives, in part, from its ability to sequester Rb and Rb family members. We report here that E1A also acts upstream of Rb by blocking the TGF-beta-mediated induction of p15 and p21. Consistent with these findings, E1A expression also blocks the ability of TGF-beta to inhibit Cdk2 kinase activity, as well as its ability to hold Rb in a hypophosphorylated state. The effect of E1A on the induction of p15 and p21 is independent of E1A's Rb binding activity. The E1A-mediated decrease in p15 levels is primarily the result of a block at the level of transcriptional activation by TGF-beta. This effect is dependent on E1A's ability to bind p300, one of E1A's target proteins. Thus, the ability of E1A to affect p15 and p21 expression represents an additional possible mechanism by which E1A can circumvent the negative regulation of cell cycle progression.
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PMID:The viral oncoprotein E1A blocks transforming growth factor beta-mediated induction of p21/WAF1/Cip1 and p15/INK4B. 912 51

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

Irreversible exit from the cell cycle precludes the ability of cardiac muscle cells to increase cell number after infarction. Using adenoviral E1A, we previously demonstrated dual pocket protein- and p300-dependent pathways in neonatal rat cardiac myocytes, and have proven that E2F-1, which occupies the Rb pocket, suffices for these actions of E1A. By contrast, the susceptibility of adult ventricular cells to viral delivery of exogenous cell cycle regulators has not been tested, in vitro or in vivo. In cultured adult ventricular myocytes, adenoviral gene transfer of E2F-1 induced expression of proliferating cell nuclear antigen, cyclin-dependent protein kinase 4, cell division cycle 2 kinase, DNA synthesis, and apoptosis. In vivo, adenoviral delivery of E2F-1 by direct injection into myocardium induced DNA synthesis, shown by 5'-bromodeoxyuridine incorporation, and accumulation in G2/M, by image analysis of Feulgen-stained nuclei. In p53(-)/- mice, the prevalence of G1 exit was more than twofold greater; however, E2F-1 evoked apoptosis and rapid mortality comparably in both backgrounds. Thus, the differential effects of E2F-1 on G1 exit in wild-type versus p53-deficient mice illustrate the combinatorial power of viral gene delivery to genetically defined recipients: E2F-1 can override the G1/S checkpoint in postmitotic ventricular myocytes in vitro and in vivo, but leads to apoptosis even in p53(-)/- mice.
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PMID:Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo. 938 35


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