Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The MUC1 oncoprotein interacts with the c-Abl tyrosine kinase and blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. Mutation of the MUC1 cytoplasmic domain at Tyr-60 disrupts the MUC1-c-Abl interaction. The present results demonstrate that the MUC1(Y60F) mutant is a potent inducer of the ARF tumor suppressor. MUC1(Y60F) induces transcription of the ARF locus by a c-Abl-dependent mechanism that promotes CUL-4A-mediated nuclear export of the replication protein Cdc6. The functional significance of these findings is that MUC1(Y60F)-induced ARF expression and thereby inhibition of MDM2 results in the upregulation of p53 and the homeodomain interacting protein kinase 2 (HIPK2) serine/threonine kinase. HIPK2-mediated phosphorylation of p53 on Ser-46 was further associated with a shift from expression of the cell cycle arrest-related p21 gene to the apoptosis-related PUMA gene. We also show that the MUC1(Y60F) mutant functions as dominant negative inhibitor of tumorigenicity. These findings indicate that the oncogenic function of MUC1 is conferred by suppressing activation of the ARF-MDM2-p53 pathway.
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PMID:MUC1 oncoprotein suppresses activation of the ARF-MDM2-p53 pathway. 1898 34

Recovery from ischaemic stroke is dependent on survival of neurones, particularly in peri-infarcted regions. Angiogenesis is critical for the development of new microvessels resulting in the re-formation of collateral circulation associated with enhanced neuronal survival and reduced morbidity and mortality. Recently, the identification of a neurovascular niche has been described, where the co-ordinated effects of angiogenesis and migration of neuroprogenitor cells to damaged stroke regions were shown to be vital in the process of tissue remodelling. Cdk5, a serine/threonine kinase is highly expressed in the central nervous system, particularly following ischaemic stroke and its aberrant activation is directly associated with neuronal apoptosis and death. In contrast, recent evidence suggests that increased expression of Cdk5 by endothelium might be protective against cell death and/or promote angiogenesis leading to increased vessel formation and reperfusion. Owing to its known interaction with over 20 substrates including caspase-3, MEF2, Tau and p53, Cdk5 could be a master switch controlling both neuronal survival and revascularisation. Therefore its cell-specific pharmacological or genetic modulation using novel nanotechnology-based delivery systems could be of benefit when considering future stroke therapies.
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PMID:Cyclin-dependent kinase-5 targeting for ischaemic stroke. 1898 42

Somatic LKB1 serine/threonine kinase alterations are rare in sporadic cancers, with the exception lung adenocarcinoma, but no mutations in squamous cell or large cell primary carcinoma were discovered. We screened the LKB1 gene in 129 primary nonsmall cell lung carcinomas, adjacent healthy lung tissue, and control blood samples. Forty-five percent of nonsmall cell lung tumors harbored either intron or exon alterations. We identified R86G, F354L, Y272Y and three polymorphisms: 290+36G/T, 386+156G/T, and 862+145C/T (novel). R86G (novel) and F354L mutations were found in six squamous cell carcinomas and three large cell cancer carcinomas, but not in the adjacent healthy tissue or controls samples. The F354L mutation was found in advanced squamous cell carcinomas with elevated COX-2 expression, rare P53, and no K-RAS mutation. Results indicate that the LKB1 gene is changed in a certain proportion of nonsmall cell lung tumors, predominately in advanced squamous lung carcinoma. Inactivation of the gene takes place via the C-terminal domain and could be related to mechanisms influencing tumor initiation, differentiation, and metastasis.
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PMID:Somatic alterations of the serine/threonine kinase LKB1 gene in squamous cell (SCC) and large cell (LCC) lung carcinoma. 1922 1

The prevalence in human cancers of mutations in p53 exemplifies its crucial role as a tumor suppressor transcription factor. Previous studies have shown that the constitutively active serine/threonine kinase glycogen synthase kinase-3beta (GSK3 beta) associates with the C-terminal basic domain of p53 and regulates its actions. In this study we identified the GSK3 beta N-terminal amino acids 78-92 as necessary for its association with p53. Inhibitors of GSK3 impaired the acetylation of p53 at Lys373 and Lys382 near the GSK3 beta binding region in p53, indicating that GSK3 beta facilitates p53 acetylation. We also found that acetylation of p53 reduced its association with GSK3 beta, as well as with GSK3alpha. These results indicate that the N-terminal region of GSK3 beta binds p53, this association promotes the acetylation of p53, and subsequently acetylated p53 dissociates from GSK3.
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PMID:GSK3 beta N-terminus binding to p53 promotes its acetylation. 1926 51

The vaccinia-related kinases (VRKs) branched off early from the family of casein kinase (CK) I and compose a relatively uncharacterized family of the kinome. The VRKs were discovered due to their close sequence relation to the vaccinia virus B1R serine/threonine kinase. They were first described in phosphorylation of transcription factors that led to the discovery of an autoregulatory mechanism between VRK and the tumor suppressor transcription factor p53. The relevance of VRKs has broadened recently by introduction of its members as essential regulators in cell signaling, nuclear envelope dynamics, chromatin modifications, apoptosis and cellular stress response. Several phosphorylation substrates have been described, as well as the first positive and negative regulators of VRK. We provide an overview of the VRKs across species and discuss the wide diversity of cellular and organismal requirements for this kinase family.
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PMID:Emerging biological functions of the vaccinia-related kinase (VRK) family. 1933 73

Mirk/Dyrk1B is a serine/threonine kinase widely expressed in colon cancers. Serum starvation induced HD6 colon carcinoma cells to enter a quiescent G0 state, characterized by a 2N DNA content and a lower RNA content than G1 cells. Compared with cycling cells, quiescent cells exhibited 16-fold higher levels of the retinoblastoma protein p130/Rb2, which sequesters E2F4 to block entry into G1, 10-fold elevated levels of the CDK inhibitor p27kip1, and 10-fold higher levels of Mirk. However, depletion of Mirk did not prevent entry into G0, but enabled quiescent HD6, SW480, and colo320 colon carcinoma cells to acquire some biochemical characteristics of G1 cells, including increased levels of cyclin D1 and cyclin D3 because of slower turnover, increased activity of their CDK4/cyclin D complexes, and increased phosphorylation and decreased E2F4 sequestering ability of the CDK4 target, p130/Rb2. As a result, depletion of Mirk allowed some cells to escape quiescence and enabled cells released from quiescence to traverse G1 more quickly. The kinase activity of Mirk was increased by the chemotherapeutic drug 5-fluorouracil (5-FU). Treatment of p53 mutant colon cancer cells with 5-FU led to an elongated G1 in a Mirk-dependent manner, as G1 was shortened by ectopic overexpression of cyclin D1 mutated at the Mirk phosphorylation site (T288A), but not by wild-type cyclin D1. Mirk, through regulating cyclin D turnover, and the CDK inhibitor p27, as shown by depletion studies, functioned independently and additively to regulate the exit of tumor cells from quiescence.
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PMID:Mirk regulates the exit of colon cancer cells from quiescence. 1954 20

The maintenance of genomic integrity is important in normal cell growth and organism development, as well as in the prevention of cancer. Cell cycle checkpoints allow the cell time to complete replication and repair DNA damage before it can pass to the next cell cycle stage. These checkpoints ensure faithful segregation of one undamaged copy of the genome to each daughter cell. In humans, a DNA damage-based checkpoint signal in G(1) is propagated through activation of the tumor suppressor p53, which is mutated in many cancers. Chk1, a serine/threonine kinase, controls checkpoint responses in G(2). Chk1 is activated by the concerted action of many upstream proteins and prevents a cell from entering mitosis with damaged or incompletely replicated DNA. This checkpoint is conserved from the fission yeast, Schizosaccharomyces pombe through to humans. However, unlike p53, G(2) checkpoint genes are rarely if ever mutated in cancer cells. This suggests that these genes are essential for tumor cell viability and may represent valid anti-cancer drug targets. This review will describe the current understanding of the G(2) checkpoint including how the human biology has been informed by studies in fission yeast. It will also discuss the present status and future of potential cancer therapies aimed at inactivating this signaling pathway in tumor cells.
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PMID:The G(2) DNA damage checkpoint: could this ancient regulator be the Achilles heel of cancer? 1957 38

Death-associated protein kinase (DAPK) is a serine/threonine kinase that contributes to pro-apoptotic signaling on cytokine exposure. The role of DAPK in macrophage-associated tumor cell death is currently unknown. Recently, we suggested a new function for DAPK in the induction of apoptosis during the interaction between colorectal tumor cells and tumor-associated macrophages. Using a cell-culture model with conditioned supernatants of differentiated/activated macrophages (U937) and human HCT116 colorectal tumor cells, we replicated DAPK-associated tumor cell death; this model likely reflects the in vivo tumor setting. In this study, we show that tumor necrosis factor-alpha exposure under conditions of macrophage activation induced DAPK-dependent apoptosis in the colorectal tumor cell line HCT116. Simultaneously, early phosphorylation of p38 mitogen-activated protein kinase (phospho-p38) was observed. We identified the phospho-p38 mitogen-activated protein kinase as a novel interacting protein of DAPK in tumor necrosis factor-alpha-induced apoptosis. The general relevance of this interaction was verified in two colorectal cell lines without functional p53 (ie, HCT116 p53(-/-) and HT29 mutant) and in human colon cancer and ulcerative colitis tissues. Supernatants of freshly isolated human macrophages were also able to induce DAPK and phospho-p38. Our findings highlight the mechanisms that underlie DAPK regulation in tumor cell death evoked by immune cells.
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PMID:RETRACTED: Identification of phosphorylated p38 as a novel DAPK-interacting partner during TNFalpha-induced apoptosis in colorectal tumor cells. 2799 39

The spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of disorders characterized by degeneration and loss of anterior horn cells in the spinal cord, leading to muscle weakness and atrophy. Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH, also known as pontocerebellar hypoplasia type 1 [PCH1]) is one of the rare infantile SMA variants that include additional clinical manifestations, and its genetic basis is unknown. We used a homozygosity mapping and positional cloning approach in a consanguineous family of Ashkenazi Jewish origin and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH. VRK1, one of three members of the mammalian VRK family, is a serine/threonine kinase that phosphorylates p53 and CREB and is essential for nuclear envelope formation. Its identification as a gene involved in SMA-PCH implies new roles for the VRK proteins in neuronal development and maintenance and suggests the VRK genes as candidates for related phenotypes.
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PMID:Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene. 1964 78

In this study, we investigated the molecular basis of Korean kidney bean husk extract, with emphasis on its ability to control intracellular signaling cascades of AMP-activated protein kinase (AMPK) responsible for inducing antitumor activities in colon cancer cells. Recently, the evolutionarily conserved serine/threonine kinase, AMPK, has emerged as a possible target molecule of tumor control. We investigated the effects of Korean kidney bean husk extract on apoptosis regulation and the activation of AMPK. Korean kidney bean husk extract exhibited a series of antitumor effects such as cell death and apoptotic body appearance. These antitumor potentials were accompanied by the increase in p-AMPK and p-Acc as well as antitumor proteins p53 and p21. The stimulation of AMPK by this extract was blocked with the synthetic AMPK inhibitor Compound C at 10 micromol/L, and the combined treatment of Compound C and the AMPK activator AICAR (5-aminoimiazole-4-carboxamide-1-beta-D-ribofuranoside) showed that Compound C could inhibit the activation of AMPK at the concentration of 20 micromol/L. In conclusion, the ability of carcinogenesis control by Korean kidney bean husk extract with high potency suggests its value as an antitumor agent in colon cancer therapy.
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PMID:Kidney bean husk extracts exert antitumor effect by inducing apoptosis involving AMP-activated protein kinase signaling pathway. 1972 93


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