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 receptor tyrosine kinase Kit and its cognate ligand KL/steel factor are encoded at the white spotting (W) and Steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl loci affect hematopoiesis including the stem cell hierarchy, erythropoiesis, and mast cells, as well as gametogenesis and melanogenesis. In addition, mutant mice display an increased sensitivity to lethal doses of irradiation. The role of KL/c-kit in cell proliferation and survival under conditions of growth factor-deprivation and gamma-irradiation was studied by using bone marrow-derived mast cells (BMMC) as a model. Whereas apoptosis induced by growth factor deprivation in BMMC is a stochastic process and follows zero order kinetics, gamma-irradiation-induced apoptosis is an inductive process and follows higher order kinetics. In agreement with these results, gamma-irradiation-induced apoptosis in BMMC was shown to be dependent on p53 whereas apoptosis induced by deprivation is partly dependent on p53, implying that there are other mechanisms mediating apoptosis in KL-deprived BMMC. In the presence and in the absence of serum, KL stimulated proliferation by promoting cell cycle progression. The presence of KL was required only during the early part of the G1 phase for entry into the S phase. At concentrations lower than those required for proliferation, KL suppressed apoptosis induced by both growth factor-deprivation and gamma-irradiation, and internucleosomal DNA fragmentation characteristic of apoptosis. The ability of KL to suppress apoptosis was independent of the phase of the cell cycle in which the cells were irradiated and suppression of apoptosis was a prerequisite for subsequent cell cycle progression. Moreover, addition of KL to gamma-irradiated and growth factor-deprived cells could be delayed for up to 1 h after irradiation or removal of growth factors when cells became irreversibly committed to apoptosis. KL and IL-3 induce suppression of apoptosis in mast cells by different mechanisms based on the observations of induction of bcl-2 gene expression by IL-3 but not by KL. It is proposed that the increased sensitivity of W and Sl mutant mice to lethal irradiation results from paucity of the apoptosis suppressing and proliferative effects of KL.
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PMID:Role of kit-ligand in proliferation and suppression of apoptosis in mast cells: basis for radiosensitivity of white spotting and steel mutant mice. 751 99

Activation of the p53 protein can lead to apoptosis and cell cycle arrest. In contrast, activation of the signalling pathway controlled by the Kit receptor tyrosine kinase prevents apoptosis and promotes cell division of a number of different cell types in vivo. We have investigated the consequences of activating the Kit signalling pathway by its ligand Steel factor on these opposing functions of the p53 protein in Friend erythroleukemia cells. A temperature-sensitive p53 allele (Val-135) was introduced into the Friend erythroleukemia cell line (DP-16) which lacks endogenous p53 expression. At 38.5 degrees C, the Val-135 protein maintains a mutant conformation and has no effect on cell growth. At 32 degrees C, the mutant protein assumes wild-type properties and induces these cells to arrest in G1, terminally differentiate, and die by apoptosis. We demonstrate that Steel factor inhibits p53-mediated apoptosis and differentiation but has no effect on p53-mediated G1/S cell cycle arrest. These results demonstrate that Steel factor functions as a cell survival factor in part through the suppression of differentiation and apoptosis induced by p53 and suggest that cell cycle arrest and apoptosis may be separable functions of p53.
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PMID:Regulation of p53-mediated apoptosis and cell cycle arrest by Steel factor. 852 62

Breast cancer prognosis has previously been linked to the degree of tumour vascularisation. In order to establish additional markers for tumour angiogenesis, we have used monoclonal antibodies against the endothelial Tie receptor tyrosine kinase to study the degree of vascularisation of breast carcinomas and the regulation of Tie expression in the vascular endothelial cells. Antibodies were used for Tie detection and the results were correlated with other prognostic markers. Of four monoclonal antibodies directed against different epitopes of the Tie extracellular domain, two reacted against Tie in unfixed histopathological sections of breast carcinomas. One of these antibodies (clone 7e8) was specific for the endothelial cells whereas the other (clone 10f11) also reacted with basement membranes and occasional carcinoma cells. When Tie expression was studied with the antibody clone 7e8, all 27 carcinomas, two in situ carcinomas, samples of histologically normal breast tissue (n = 16) or normal skin or lymph node tissue (n = 5) showed staining. Microvessel counts were higher in carcinomas (median 14; range 3-27) than in fibrodenomas (median 10; range 5-18) or histologically normal breast tissue (median 7; range 3-15, P = 0.0006). A similar result was obtained using antibodies against the CD31 (PECAM) antigen. Microvessel counts in 7e8 staining were not significantly associated with primary tumour size, axillary nodal status, histological grade or staining for oestrogen receptor, progesterone receptor, Ki-67 proliferation marker or p53 oncoprotein.
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PMID:Endothelial Tie growth factor receptor provides antigenic marker for assessment of breast cancer angiogenesis. 867 61

Genotoxic stress triggers signalling pathways that mediate either the protection or killing of affected cells. Whereas induction of p53 involves events in the cell nucleus, the activation of transcription factors AP-1 and NF-kappaB by ultraviolet radiation is mediated through membrane-associated signalling proteins, ruling out a nuclear signal. An early event in AP-1 induction by ultraviolet radiation is activation of Jun kinases (JNKs), which mediate the induction of the immediate-early genes c-jun and c-fos. The JNKs have also been proposed to mediate the apoptopic response to genotoxins. The non-receptor tyrosine kinase c-Abl is also activated by genotoxic stress. To understand the relationship between these events, we compared the activation of p53, JNK and c-Abl by several DNA-damaging agents in murine fibroblasts. We found that whereas p53 was induced by every genotoxic stimulus tested, c-Abl was activated by most stimuli except ultraviolet irradiation and JNK was strongly stimulated only by ultraviolet light and the alkylating agent methyl methanesulphonate. Activation of JNK by this alkylating agent was normal in c-Abl-null cells but was reduced in c-Src-null cells. Unlike p53 induction, c-Abl activation occurs in the S phase of the cell cycle and does not affect cell proliferation. These findings show that signals generated by genotoxins are transduced by multiple, independent pathways. Only p53 appears to be a universal sensor of genotoxic stress.
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PMID:Three distinct signalling responses by murine fibroblasts to genotoxic stress. 891 68

Fas-mediated cell death was examined in MCF-10AT preneoplastic human breast epithelial cells. Treatment with anti-Fas for 48 h induced apoptosis with cells exhibiting typical apoptotic features including loss of cell contact, condensation of chromatin, and increased staining of the nuclear membrane. DNA fragmentation occurred in response to anti-Fas treatment. Anti-Fas treatment resulted in decreased p53 protein levels, while bcl-2 and bax protein levels remained unaffected. Cells treated with anti-Fas also exhibited increased tyrosine phosphorylation of the c-met growth factor receptor tyrosine kinase. Immunoprecipitation experiments demonstrated that Fas associated with c-erbB2 and c-met in untreated cells. Treatment with anti-Fas, however, significantly decreased Fas-c-erbB2 and Fas-c-met association. Anti-Fas treatment of these cells caused a significant decrease in p120-GAP levels, ERK-1 levels, and phosphorylation, as well as Grb2-Sosl and MEK-1-ERK-1 association. These results show that Fas-signaling exerted a suppressive effect on p53 levels and on downstream effectors of receptor tyrosine kinase signal transduction, thereby ensuring cell death.
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PMID:Fas-signaling and effects on receptor tyrosine kinase signal transduction in human breast epithelial cells. 902 68

Mice bred to carry germline Rb and p53 null alleles are associated with a tumor spectrum that overlaps with the inherited multiple endocrine neoplasia-1 (MEN1) and MEN2 syndromes in humans, including medullary thyroid cancer (MTC). To study the genetic basis for these tumors, we microdissected MTC specimens or obtained fresh MTC tissue from nine independent Rb(+/-) p53(+/-) mice, amplified the region of the Ret gene known to be mutated in human MTC, and detected acquired missense Ret mutations in four different mice. These mutations were localized to a group of tandem cysteines which are analogous to activating germline mutations observed in human MEN2A and familial MTC (FMTC). To determine whether the remaining wild type Rb allele was inactivated in these murine MTC samples, we subjected tumor tissue to immunohistochemical staining with an Rb antibody, and demonstrated the absence of RB staining in murine MTC, while normal tissue retained RB nuclear staining. These findings demonstrate the ability of the gene knockout model to recapitulate somatic multi-step tumorigenesis and suggest that the development of a murine neuroendocrine tumor requires mutational dysregulation within both receptor tyrosine kinase and nuclear tumor suppressor gene pathways.
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PMID:RET cooperates with RB/p53 inactivation in a somatic multi-step model for murine thyroid cancer. 979 40

The KIT protein is a receptor tyrosine kinase of the platelet derived growth factor (PDGF) receptor family which regulates haematopoiesis, melanogenesis and gut and germ cell development. KIT regulates these diverse processes, at least in part, by inhibiting apoptosis. We have previously found that KIT can suppress p53-mediated apoptosis. The mechanism by which KIT suppresses apoptosis is, however, uncharacterized. Neither is it clear how p53 induces apoptosis. In this report we find that p53-dependent apoptosis proceeds through a pathway involving depolarization of the mitochondrial electropotential gradient (delta(psi)m) and the generation of reactive oxygen species (ROS). KIT activation suppresses p53-induced apoptosis in the mouse DP16 Friend erythroleukemia cell line by preventing delta(psi)m depolarization and ROS generation. Thus, the KIT kinase prevents apoptosis by regulating mitochondrial function and cellular redox state.
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PMID:Inhibition of p53-dependent apoptosis by the KIT tyrosine kinase: regulation of mitochondrial permeability transition and reactive oxygen species generation. 979 94

c-Abl, a non-receptor tyrosine kinase, is activated by agents that damage DNA. This activation results in either arrest of the cell cycle in phase G1 or apoptotic cell death, both of which are dependent on the kinase activity of c-Abl. p73, a member of the p53 family of tumour-suppressor proteins, can also induce apoptosis. Here we show that the apoptotic activity of p73alpha requires the presence of functional, kinase-competent c-Abl. Furthermore, p73 and c-Abl can associate with each other, andthis binding is mediated by a PxxP motif in p73 and the SH3 domain of c-Abl. We find that p73 is a substrate of the c-Abl kinase and that the ability of c-Abl to phosphorylate p73 is markedly increased by gamma-irradiation. Moreover, p73 is phosphorylated in vivo in response to ionizing radiation. These findings define a pro-apoptotic signalling pathway involving p73 and c-Abl.
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PMID:Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis. 1039 Dec 35

Mutations of the receptor tyrosine kinase, Kit, or its ligand, mast growth factor (Mgf), affect three unrelated cell populations: melanocytes, germ cells, and mast cells. Kit signaling is required initially to prevent cell death in these lineages both in vitro and in vivo. Mgf appears to play a role in the survival of some hematopoietic cells in vitro by modulating the activity of p53. Signaling by Mgf inhibits p53-induced apoptosis of erythroleukemia cell lines and suppresses p53-dependent radiation-induced apoptosis of bone marrow cells. We tested the hypothesis that cell survival in Kit mutant mice would be enhanced by p53 deficiency in vivo. Double-mutant mice, which have greatly reduced Kit receptor tyrosine kinase activity and also lack Trp53, were generated and the affected cell lineages examined. Mast cell, melanoblast, and melanocyte survival in the double Kit(W-v/W-v):Trp53(-/-) mutants was not increased compared to the single Kit(W-v/W-v):Trp53(+/+) mutants. However, double-mutant males showed an increase in sperm viability and could father litters, in contrast to their homozygous Kit mutant, wild-type p53 littermates. This germ cell rescue appears to be male specific, as female ovaries were similar in mice homozygous for the Kit mutant allele with or without p53. We conclude that defective Kit signaling in vivo results in apoptosis by a p53-independent pathway in melanocyte and mast cell lineages but that in male germ cells apoptosis in the absence of Kit is p53-dependent.
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PMID:Deficiency of Trp53 rescues the male fertility defects of Kit(W-v) mice but has no effect on the survival of melanocytes and mast cells. 1052 51

We evaluated F3 mouse offspring from paternal F0 attenuated 137Cs gamma-irradiation (1.0 Gy) for heritable effects on gene products that can modulate cell proliferation rate and that may be markers for genomic instability. The F3 generation was selected for evaluation as a stringent test for heritability of effects from paternal F0 germline irradiation. Male CD1 mice were bred 6 weeks after irradiation so that the fertilizing sperm were type B spermatogonia at the time of irradiation. The resulting F1 males were bred to CD1 females to produce F2 four-cell embryos. The F2 embryos with a radiation history were paired with 'control' CD1 four-cell embryos that were heterozygous for the neo transgene. These F2 XY-XY chimeras, consisting of cells derived from both an embryo with a paternal F0 radiation history and a control embryo, were transferred to foster mothers, raised to adulthood and bred to produce F3 offspring. F3 offspring were evaluated for hepatic activities of receptor tyrosine kinase, protein kinase C and MAP kinase and for protein levels of nuclear p53 and p21(waf1). All three protein kinase activities were altered and nuclear levels of p53 and p21(waf1) protein were higher in the group of offspring that included F3 offspring with a paternal F0 radiation history than in littermates in the neo-positive control group. To our knowledge, this is the first observation in the descendants of paternal germline irradiation of effects on signal protein kinase activities and downstream nuclear target proteins that can influence cell proliferation rates.
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PMID:Heritable effects of paternal irradiation in mice on signaling protein kinase activities in F3 offspring. 1113 95


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