Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43146 (tumour suppressor)
 5,935 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 tumour suppressor protein is thought to play a major role in the defence of the cell against agents which damage DNA. p53 is phosphorylated at multiple sites in vivo and by several different protein kinases in vitro. In this report, we have examined the phosphorylation of murine p53 by protein kinase C (PKC). Phosphopeptide mapping, phosphoamino acid analysis and radiosequence analysis of p53 phosphorylated by PKC in vitro indicated that serine 370 and threonine 377 were the major targets for phosphorylation and suggested that serine 372 and threonines 365 and 371 were minor phosphorylation sites. Site-directed mutagenesis confirmed that residues 370-372, all of which lie within the epitope for monoclonal antibody PAb421, were phosphorylated in vitro. The p53 from 32P-labelled SV3T3 cells showed a phosphopeptide pattern which includes peptides with mobilities similar to those arising from phosphorylation of residues 370-372 by PKC in vitro. Only two of these in vivo-labelled phosphopeptides co-migrated in two dimensions with peptides labelled in vitro within the PAb421 epitope and their phosphorylation was not stimulated by the addition of the PKC activator o-tetradecanoylphorbol 13-acetate (TPA) to the cells, even though this treatment led to a fourfold stimulation of p53 phosphorylation by MAP kinase. Moreover, when the p53 proteins containing mutations at residues 370-372 were expressed in COS cells, there was no loss of any of the in vivo phosphopeptides, indicating that phosphorylation within the PAb42I epitope was undetectable in the cell. These data suggest that p53 and PKC may not interact in vivo. The two-dimensional migration pattern of the novel group of peptides is consistent with phosphorylation of previously uncharacterised sites within the central DNA binding region of p53.
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PMID:Murine p53 is phosphorylated within the PAb421 epitope by protein kinase C in vitro, but not in vivo, even after stimulation with the phorbol ester o-tetradecanoylphorbol 13-acetate. 870 May 48

The hepatitis B virus (HBV) genome encodes a 154 amino acid protein termed X (HBx, hepatitis B x protein), which is a promiscuous transcriptional activator of polymerase II and III promoters. HBx upregulates a wide range of cellular and viral genes and is thought to facilitate viral pregenome and mRNA transcription; however, its precise role in the viral replication cycle remains to be elucidated. The functional mechanisms of HBx appear very complex. It was shown to activate transcription factors AP-1 and NF-kappa B vis cytoplasmic pathways including ras-MAP kinase. In contrast, nuclear HBx is thought to activate the transcriptional machinery directly. A second transcriptional activator protein (Mst, middle s transactivator) is encoded by 3'-truncated preS2/S sequences of integrated HBV DNA, but not by the intact viral gene. HBx and Mst may contribute to the pathogenicity of chronic hepatitis B and are suggested to promote hepatocyte transformation via upregulation of cellular proto-oncogenes. Further, HBx may enhance HBV related carcinogenesis by inactivation of the tumour suppressor gene product p53.
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PMID:Hepatitis B virus transcriptional activators: mechanisms and possible role in oncogenesis. 887 69

The growth suppressive activity of the retinoblastoma tumour suppressor protein is controlled by cell cycle dependent phosphorylation. However, while many in vivo phosphorylation sites have been mapped, the identities of those residues whose phosphorylation is regulated remain elusive. We have mapped the epitopes of three independent monoclonal antibodies that recognise a distinction between differentially phosphorylated pRB sub-populations. All three antibodies recognise an identical epitope which encompasses an essential serine positioned within a consensus site for proline directed kinase phosphorylation. We provide evidence that this residue, serine 608 of pRB, is an authentic phosphorylation site that can be phosphorylated in vitro by cyclin A-CDK2 and cyclin D1-CDK4 kinases but not by cyclin E-CDK2 kinase or the mitogen activated kinase ERK2. Phosphorylation at this residue seems to be cell cycle regulated, occurring prior to entry into the S phase.
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PMID:Monoclonal antibodies specific for underphosphorylated retinoblastoma protein identify a cell cycle regulated phosphorylation site targeted by CDKs. 901 Feb 27

Studies of the roles of oncoproteins in cell cycle progression have concentrated on G1 because transformation is frequently associated with loss of G1 checkpoint control. However, it has become evident that G2 and mitotic checkpoints are often compromised in transformed cells and that many tumour suppressor proteins and oncoprotein kinases regulate and/or are activated in G2 and M. Disruption of p53 and ATM tumour suppressor protein functions can eliminate G2 and M checkpoints. The Src family kinases are activated in mitosis and collectively play an indispensable role in progression through G2/M. In addition, evidence suggests that Mos and elements of the Ras/Raf/MAPK cascade are also active in mitosis and appear likely to regulate G2 and/or M. Potential targets of these kinases include likely regulators of gene expression and microtubule dynamics such as Sam68 and Oncoprotein 18/stathmin. The ability of some oncoproteins to perturb orderly progression through both G1 and/or S and G2 and/or M is probably important for transformation.
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PMID:Oncoprotein signalling and mitosis. 921 24

The p53 tumour suppressor protein is tightly regulated by protein-protein association, protein turnover and a variety of post-translational modifications. Multisite phosphorylation plays a major role in activating and in finely tuning p53 function. The proline rich domain of murine p53 is a substrate for phosphorylation, in vitro and in cultured cells, by the p42ERK2 and p44ERK1 mitogen-activated protein (MAP) kinases. However, to date there have been no reports of attempts to determine whether p53 from any other species is a substrate for MAP kinase. In this paper we confirm that murine p53 is targeted by recombinant MAP kinase and by MAP kinases in extracts of both murine and human cells. In contrast, human p53 is not a substrate for recombinant MAP kinase nor are there any detectable levels of protein kinase activity in stimulated human cell extracts which phosphorylate the proline rich domain of human p53 in vitro. Finally, although stimulation of murine fibroblasts with o-tetradecanolylphorbol 13-acetate (TPA), an indirect activator of the MAP kinase pathway, leads to site-specific phosphorylation of murine p53, similar treatment of human fibroblasts and epithelial cells showed no significant changes in the phosphorylation pattern. These data are consistent with accumulating evidence that significant species-dependent differences exist in the post-translational modification of p53.
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PMID:Phosphorylation of murine p53, but not human p53, by MAP kinase in vitro and in cultured cells highlights species-dependent variation in post-translational modification. 1060 21

Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The pathogenesis of HBV-induced malignant transformation is, however, incompletely understood. HBx, the protein encoded by the X open reading frame, is a transcriptional activator that has been implicated in hepatocarcinogenesis. HBx inhibits the function of the tumour suppressor protein p53 in what is thought to be an early event in hepatocyte transformation before the later accumulation of inactivating p53 point mutations. HBx inhibits apoptosis but also exerts pro-apoptotic effects. The effects of HBx on apoptosis may be important not only for the development of HCC but also for the establishment of HBV infection. Further implication of HBx in hepatocyte transformation has been the demonstration that it inhibits the repair of damaged hepatocyte DNA. This effect may be mediated by interaction with p53 or through binding to the damaged DNA binding protein (DDB), which plays an accessory role in nucleotide excision repair. In addition, HBx activates cell signalling cascades involving mitogen-activated protein kinase (MAPK) and Janus family tyrosine kinases (JAK)/signal transducer and activators of transcription (STAT) pathways. The implications of these modulating effects of HBx are not fully understood, but they are likely to have wide-ranging effects on hepatocyte proliferation, apoptosis and the regulation of cell growth checkpoints. The cellular functions ascribed to HBx are unusually diverse, and defining the biologically important role of HBx during HBV replication will go some way to understanding the sequelae of chronic HBV infection.
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PMID:Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. 1082 73

Apoptosis is a normal physiological process which eliminates cells that do not receive adequate extracellular signals. One of the pathways signalling apoptosis is controlled by the small GTPases of the Rho family, also involved in cell proliferation, differentiation and motility. Another major apoptosis signalling pathway involves the p53 tumour suppressor which is activated by a variety of stress and mediates growth arrest or apoptosis in normal cells. We show here that upon detachment from the extracellular matrix, fibroblasts undergo rapid apoptosis that can be rescued by constitutive activation of Rac1 and Cdc42Hs GTPases. Conversely, inhibition of Rac1 and Cdc42Hs efficiently triggers apoptosis in adherent cells. Interestingly, apoptosis is not observed in p53-/- cells either cultured in suspension or inhibited for Rac1 and Cdc42Hs activity. Moreover, Rac1 and Cdc42Hs extinction in normal cells activates endogenous p53. Using specific inhibitors of MAPK pathways, we demonstrate that, in our experimental system, p38 signals survival, while ERK activity is required for apoptosis. Our data constitute the first demonstration that Rac1 and Cdc42Hs control pathways that require simultaneous signalling through MAPK ERK and p53 to induce apoptosis.
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PMID:Extinction of rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway. 1082 79

The tumour suppressor gene PTEN encodes a dual-specificity phosphatase that recognizes protein substrates and phosphatidylinositol-3,4,5-triphosphate. PTEN seems to play multiple roles in tumour suppression and the blockade of phosphoinositide-3-kinase signalling is important for its growth suppressive effects, although precise mechanisms are not fully understood. In this study, we show that PTEN plays a unique role in the insulin-signalling pathway in a breast cancer model. Ectopic expression of wild-type PTEN in MCF-7 epithelial breast cancer cells resulted in universal inhibition of Akt phosphorylation in response to stimulation by diverse growth factors and selective inhibition of MEK/extracellular signal-regulated kinase (ERK) phosphorylation stimulated by insulin or insulin-like growth factor 1 (IGF-1). The latter was accompanied by a decrease in the phosphorylation of insulin receptor substrate 1 (IRS-1) and the association of IRS-1 with Grb2/Sos, without affecting the phosphorylation status of the insulin receptor and Shc, nor Shc/Grb2 complex formation. The MEK inhibitor, PD980059, but not the PI3K inhibitor, wortmannin, abolished the effect of PTEN on insulin-stimulated cell growth. Without addition of insulin, wortmannin reduced PTEN-mediated growth suppression, whereas PD980059 had little effect, suggesting that PTEN suppresses insulin-stimulated cell growth by blocking the mitogen-activated protein kinase (MAPK) pathway. Furthermore, PD980059 treatment led to the downregulation of cyclin D1 and the suppression of cell cycle progression. Our data suggest that PTEN blocks MAPK phosphorylation in response to insulin stimulation by inhibiting the phosphorylation of IRS-1 and IRS-1/Grb2/Sos complex formation, which leads to downregulation of cyclin D1, inhibition of cell cycle progression and suppression of cell growth.
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PMID:PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. 1123 Jan 80

In tumorigenesis of the skin, activated Ras co-operates with mutations that inactivate the tumour suppressor p53, but the molecular basis for this co-operation remains unresolved. Here we show that activation of the Raf/MAP kinase pathway in primary mouse keratinocytes leads to a p53 and p21Cip1-dependent cycle arrest and to terminal differentiation. Raf activation in keratinocytes lacking p53 or p21Cip1 genes leads to expression of differentiation markers, but the cells do not cease to proliferate. Thus, loss of p53 or p21Cip1 function is necessary to disable growth-inhibitory Raf/MAP kinase signalling. Activation of oncogenes, including Ras, has been reported to stabilize and activate p53 via induction of the tumour suppressor p19ARF. However, the response to Raf in p19ARFI-/- keratinocytes was indistinguishable from wild-type controls. Thus, p19ARF is not essential for Raf-induced p53 induction and cell cycle arrest in keratinocytes, indicating that oncogenes engage p53 activity via multiple mechanisms.
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PMID:p19ARF-independent induction of p53 and cell cycle arrest by Raf in murine keratinocytes. 1125 7

beta-Amyloid (A beta) peptide has been shown to induce neuronal apoptosis; however, the mechanisms underlying A beta-induced neuronal cell death remain to be fully elucidated. The stress-activated protein kinase, c-Jun N-terminal kinase (JNK), is activated in response to cellular stress and has been identified as a proximal mediator of cell death. In the present study, expression of active JNK was increased in the nucleus and cytoplasm of A beta-treated cells. Evaluation of the nature of the JNK isoforms activated by A beta revealed a transient increase in JNK1 activity that reached its peak at 1 h and a later activation (at 24 h) of JNK2. The tumour suppressor protein, p53, is a substrate for JNK and can serve as a signalling molecule in apoptosis. In cultured cortical neurons, we found that A beta increased p53 protein expression and phosphorylation of p53 at Ser(15). Thus it appears that A beta increases p53 expression via phosphorylation-mediated stabilization of the protein. Given the lack of availability of a JNK inhibitor that can distinguish between JNK1- and JNK2-mediated effects, we employed antisense technology to deplete cells of JNK1 or JNK2 selectively. Using this strategy, the respective roles of JNK1 and JNK2 on the A beta-mediated activation of the apoptotic cascade (i.e. p53 stabilization, caspase 3 activation and DNA fragmentation) were examined. The results obtained demonstrate a role for JNK1 in the A beta-induced stabilization of p53, activation of caspase 3 and DNA fragmentation. In contrast, depletion of JNK2 had no effect on the proclivity of A beta to activate capase 3 or induce DNA fragmentation. These results demonstrate a significant role for JNK1 in A beta-mediated induction of the apoptotic cascade in cultured cortical neurons.
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PMID:A role for c-Jun N-terminal kinase 1 (JNK1), but not JNK2, in the beta-amyloid-mediated stabilization of protein p53 and induction of the apoptotic cascade in cultured cortical neurons. 1253 44


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