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 p127 tumour suppressor protein encoded by the lethal(2)giant larvae, [l(2)gl], gene of Drosophila melanogaster is a component of a cytoskeletal network distributed in both the cytoplasm and on the inner face of the plasma membrane. The p127 protein forms high molecular mass complexes consisting mainly of homo-oligomerized p127 molecules and at least ten additional proteins. One of these proteins has been recently identified as nonmuscle myosin type II heavy chain. To determine the functional interactions between p127 and other proteins present in the p127 complexes, we analyzed p127 for posttranslational modifications and found that p127 can be phosphorylated at serine residues. In this report we describe the characteristics of a serine kinase which is associated with p127, as judged by its recovery in p127 complexes purified by either gel filtration or immuno-affinity chromatography. This kinase phosphorylates p127 in vitro and its activation by supplementing ATP results in the release of p127 from the plasma membrane. Moreover, similar activation of the kinase present in immuno-purified p127 complexes dissociates nonmuscle myosin II from p127 without affecting the homo-oligomerization of p127. This dissociation can be inhibited by staurosporine and a 26mer peptide covering amino acid positions 651 to 676 of p127 and containing five serine residues which are evolutionarily conserved from Drosophila to humans. These results indicate that a serine-kinase tightly associated with p127 regulates p127 binding with components of the cytoskeleton present in both the cytoplasm and on the plasma membrane.
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PMID:A serine-kinase associated with the p127-l(2)gl tumour suppressor of Drosophila may regulate the binding of p127 to nonmuscle myosin II heavy chain and the attachment of p127 to the plasma membrane. 879 24

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.
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PMID:Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. 928 6

Human papillomavirus (HPV) 16 E6 induces the degradation of the tumour suppressor protein p53 by the ubiquitin-dependent proteolysis pathway. In vitro, this process involves the formation of a trimolecular complex between E6, p53 and a cellular protein E6-associated protein (E6-AP). However, an analysis of their potential interactions in vivo has not been carried out. We have established a model for the expression and analysis of the interactions of these three proteins in insect cells, a eukaryotic system where potentially crucial modifications of the proteins will occur. In baculovirus-infected cells the degradation of p53 can occur. However, p53 is only degraded early in the infectious cycle due to a lack of ATP at later times. Consequently, substantial quantities of material can be produced in this system for further analysis. Evidence is also provided that, in vivo, E6 can interact with p53 in the absence of E6-AP and that E6-AP can interact with p53 in the absence of E6. Furthermore, analysis of the subcellular localization of the proteins using both biochemical fractionation and indirect immunofluorescence suggests that the degradation of p53 occurs in the perinuclear region of the cell.
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PMID:Characterization of the interactions of human papillomavirus type 16 E6 with p53 and E6-associated protein in insect and human cells. 951 27

The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the cell cycle and their inhibitor, the p16INK4a tumour suppressor, have a central role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to p16INK4a and to the related p19INK4d reveal that the INK4 inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin binding indirectly by causing structural changes that propagate to the cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D complexes as well. Tumour-derived mutations in INK4a and Cdk4 map to interface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16INK4a.
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PMID:Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. 975 Oct 50

Chromatin organization plays a key role in the regulation of gene expression. The evolutionarily conserved SWI/SNF complex is one of several multiprotein complexes that activate transcription by remodelling chromatin in an ATP-dependent manner. SWI2/SNF2 is an ATPase whose homologues, BRG1 and hBRM, mediate cell-cycle arrest; the SNF5 homologue, INI1/hSNF5, appears to be a tumour suppressor. A search for INI1-interacting proteins using the two-hybrid system led to the isolation of c-MYC, a transactivator. The c-MYC-INI1 interaction was observed both in vitro and in vivo. The c-MYC basic helix-loop-helix (bHLH) and leucine zipper (Zip) domains and the INI1 repeat 1 (Rpt1) region were required for this interaction. c-MYC-mediated transactivation was inhibited by a deletion fragment of INI1 and the ATPase mutant of BRG1/hSNF2 in a dominant-negative manner contingent upon the presence of the c-MYC bHLH-Zip domain. Our results suggest that the SWI/SNF complex is necessary for c-MYC-mediated transactivation and that the c-MYC-INI1 interaction helps recruit the complex.
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PMID:c-MYC interacts with INI1/hSNF5 and requires the SWI/SNF complex for transactivation function. 1031 72

The mammalian SWI/SNF complex is a chromatin remodelling complex that uses the energy of ATP hydrolysis to facilitate access of transcription factors to regulatory DNA sequences. This complex, that was initially described as a co-factor for nuclear receptors, has recently been associated with the control of cell growth. Two of the subunits known as BRG-1 and brm can associate with the Retinoblastoma tumour suppressor gene product and co-operate with this protein for repression of E2F activity. In addition, expression of brm is frequently down-regulated upon cellular transformation and re-introduction of this protein into fibroblasts transformed by activated ras induces partial reversion of the transformed phenotype. Finally, the hSNF5/INI1 gene, encoding another subunit of the SWI/SNF complex, is subject to bi-allelic mutations in rhabdoid tumours, a very aggressive form of paediatric cancers. These observations provide a novel link between malignant transformation and chromatin remodelling machineries.
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PMID:The mammalian SWI/SNF complex and the control of cell growth. 1044 Oct 69

Diadenosine oligophosphates are ubiquitous compounds that were discovered over 30 years ago. Diadenosine 5',5"'-P(1), P(4)-tetraphosphate (Ap(4)A) is the most studied member of this family, and its function in yeast is unknown. To investigate possible functions, we changed the intracellular Ap(4)A concentration in Schizosaccharomyces pombe via disruption and overexpression of the aph1 gene, which encodes an Ap(4)A hydrolase (Aph1). S. pombe Aph1 is 52% identical with a human tumour suppressor protein, Fhit, in a core region of 109 amino acids. Disruption of aph1 resulted in an 85% decrease in Ap(4)A hydrolase activity and a 290-fold increase in the intracellular Ap(4)A concentration. The disruption and subsequent increase in intracellular Ap(4)A concentration had no significant effect on the growth of S. pombe. Overexpression of the S. pombe aph1 gene, resulting in 17- and 84-fold increases in Ap(4)A hydrolase activity above wild-type levels, resulted in 60 and 80% decreases respectively in the intracellular Ap(4)A concentration. This represents the first report of a decrease in the intracellular Ap(4)A concentration in response to overexpression of a degradative enzyme in any eukaryotic organism. We describe a new S. pombe expression plasmid, pPOX, which was used to achieve the largest increase in expression of aph1. Overexpression of aph1 at the highest level resulted in a 46% increase in generation time in comparison with the control strain. Neither overexpression nor disruption had any effect on the intracellular ATP or ADP concentrations. This is the first report of ADP and ATP concentrations in S. pombe. These data also indicate that Aph1 functions in vivo to degrade Ap(4)A, and that high-level overexpression of this enzyme reduces the growth rate.
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PMID:Disruption and overexpression of the Schizosaccharomyces pombe aph1 gene and the effects on intracellular diadenosine 5',5'''-P1, P4-tetraphosphate (Ap4A), ATP and ADP concentrations. 1097 Jul 77

Initiation, progression, and completion of the cell cycle are regulated by various cyclin-dependent kinases (CDKs), which are thus critical for cell growth. Tumour development is closely associated with genetic alteration and deregulation of CDKs and their regulators, suggesting that inhibitors of CDKs may be useful anti-cancer therapeutics. Indeed, early results suggest that transformed and normal cells differ in their requirement for e.g. cyclin/CDK2 and that it may be possible to develop novel antineoplastic agents devoid of the general host toxicity observed with conventional cystostatic drugs. Numerous active-site inhibitors of CDKs have been studied; the main limitation with these ATP antagonists is kinase specificity for CDKs. However, screening of compound collections, as well as rational design based on enzyme-ligand complex crystal structures, are now yielding pre-clinical candidates, particularly certain purine and flavonoid analogues, with impressive potency and selectivity. Natural CDK inhibitors (CKIs), e.g. the tumour suppressor gene products p16(INK4), p21(WAF1), and p27(KIP1), form the starting point for the design of mechanism-based CDK inhibitors. A number of these small proteins have been dissected and inhibitory lead peptides amenable to peptidomimetic development have been identified. Conversion of these peptides into pharmaceutically useful molecules is greatly aided by the recent elucidation of CKI/CDK crystal and solution structures. Additional interaction sites on CDKs being exploited for the purposes of inhibitor design include: phosphorylation/dephosphorylation sites, macromolecular substrate binding site, CKS regulatory subunit binding sites, cyclin-binding site, cellular localisation domain, and destruction box. Finally, progress has recently been made in the application of antisense technology in order to target CDK activity.
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PMID:Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. 1103 68

Peutz-Jeghers syndrome is an inherited cancer syndrome, which results in a greatly increased risk of developing tumours in those affected. The causative gene encodes a nuclear-localized protein kinase, termed LKB1, which is predicted to function as a tumour suppressor. The mechanism by which LKB1 is regulated in cells is not known, and nor have any of its physiological substrates been identified. Recent studies have demonstrated that LKB1 is phosphorylated in cells. As a first step towards identifying the roles that phosphorylation of LKB1 play, we have mapped the residues that are phosphorylated in human embryonic kidney (HEK)-293 cells, as well as the major in vitro autophosphorylation sites. We demonstrate that LKB1 expressed in HEK-293 cells, in addition to being phosphorylated at Ser(431), a previously characterized phosphorylation site, is also phosphorylated at Ser(31), Ser(325) and Thr(366). Incubation of wild-type LKB1, but not a catalytically inactive mutant, with manganese-ATP in vitro resulted in the phosphorylation of LKB1 at Thr(336) as well as at Thr(366). We were unable to detect autophosphorylation at Thr(189), a site previously claimed to be an LKB1 autophosphorylation site. A catalytically inactive mutant of LKB1 was phosphorylated at Ser(31) and Ser(325) in HEK-293 cells to the same extent as the wild-type enzyme, indicating that LKB1 does not phosphorylate itself at these residues. We show that phosphorylation of LKB1 does not directly affect its nuclear localization or its catalytic activity in vitro, but that its phosphorylation at Thr(336), and perhaps to a lesser extent at Thr(366), inhibits LKB1 from suppressing cell growth.
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PMID:Identification and characterization of four novel phosphorylation sites (Ser31, Ser325, Thr336 and Thr366) on LKB1/STK11, the protein kinase mutated in Peutz-Jeghers cancer syndrome. 1185 58

Mutations in the core domain of the tumour suppressor p53 gene occur in over 50% of human cancers and are not present in normal cells hence p53 protein is a prime target for anti-cancer therapy. In full-length p53 protein, mutations have been shown to destabilize protein structure from wild-type to mutant conformation resulting in differential exposure of conformational epitopes PAb1620, PAb240 and PAb246 in murine p53 protein. In recent studies, putative anti-cancer agents have been designed for rescuing wild-type p53 conformation and function. Using full-length and truncated murine p53 proteins derived from the baculoviral system, we analyzed the recovery of PAb246 and PAb1620 epitopes and have identified regions of p53 required for optimal renaturation in vitro to wild-type. The influence of ATP and ADP on the process was also determined. We demonstrate a difference in the dose-dependent effect of ATP and ADP on renaturation of full-length wild-type and monomeric p53 proteins. Putative ATP binding sites were identified at residues 1-67 and 98-303 in conjunction with a putative ADP binding site at residues 98-303 and negative regulation of ATP/ADP binding by the proline-rich region. Improved efficacy and reduced toxicity of anti-cancer therapy may depend upon compounds engineered to rescue hot-spot core mutations in the context of full-length p53.
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PMID:Restoration of wild-type conformation to full-length and truncated p53 proteins: specific effects of ATP and ADP. 1532 74


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