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 role of the lyn product (p53/p56lyn), a membrane-associated protein tyrosine kinase in the signaling pathway used by granulocyte macrophage-CSFR (GM-CSFR) was investigated by using the GM-CSF-dependent human megakaryoblastic leukemia cell line M-07e. M-07e cells express GM-CSFR and are dependent on GM-CSF for survival and proliferation in vitro. Treatment with anti-lyn Abs coimmunoprecipitated, along with lyn product, the beta subunit of GM-CSFR and a phosphoprotein with a molecular mass of 120 kDa (p120) in the lysates of M-07e cells but not in the lysates of human monocyte-derived macrophages (HMDM) or human lymphoid leukemia cells. That the 120-kDa phosphoprotein coimmunoprecipitated by anti-lyn Abs is the beta subunit of GM-CSFR was confirmed in the immunoprecipitates (IP) of M-07e cells with the use of an agarose-conjugated anti-p-tyr mAb. The formation of GM-CSF/GM-CSFR/lyn signaling complexes was verified in an autoradiographic study with anti-lyn IP of M-07e cells that had been bound with 125I-labeled recombinant human (rh)GM-CSF. The p120 protein (beta subunit) was not detected in the IP of M-07e cells with anti-fyn or anti-PI3 Abs. A direct association of Lyn kinase with the beta subunit of GM-CSFR was illustrated with a reversed approach showing the recovery of Lyn protein in anti-beta (CRS1) but not anti-alpha IP of M-07e cells that had been starved for a prolonged period. Finally, the interaction of Lyn kinase with the GM-CSFR complexes was further corroborated using anti-GM-CSF (G133) mAb, which coimmunoprecipitated both the p120 beta subunit and lyn product in the lysates of M-07e cells that had been bound with rhGM-CSF before cell lysis. Removal of rhGM-CSF from culture medium for 10 to 12 h resulted in a marked decrease in lyn-associated kinase activity but not the beta subunit/lyn kinase complex formation. Taken together, our results showed that, in M-07e cells, Lyn protein tyrosine kinase (p53/p56lyn) is stably associated with a constitutively phosphorylated beta subunit of the GM-CSFR in a manner that seems to be independent of lyn kinase activity.
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PMID:Association between Lyn protein tyrosine kinase (p53/56lyn) and the beta subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors in a GM-CSF-dependent human megakaryocytic leukemia cell line (M-07e). 763 65

Apoptosis is a morphologically and biochemically distinct form of cell death which can be triggered by a variety of extracellular agents during both normal development as well as in adult pathological states. Much progress has recently been made in understanding the molecular pathways which regulate this process as well as new intersections between these. A direct interaction between components of the 'executioner'--the ICE-family of cysteine proteases--and the Bcl-2 family of proteins, which modulate a cell's propensity to undergo apoptosis, has recently been demonstrated. New pathways to cell survival, like the PI3-K/Akt signal transduction pathway, are also providing new clues as to the regulation of cell death by growth factors and extracellular matrix for example. The links which exist between apoptosis and cancer research are several. Genetic alterations in components of the apoptosis pathway occur during tumorigenesis and confer resistance to a variety of physiological (oncogene-induced cell death, loss of adhesion, growth under hypoxia) as well as therapeutic (chemotherapy and radiation) death triggers. Similarly, antineoplastic therapies are thought to induce tumor cell apoptosis, and consequently, common mutations in apoptosis-regulatory genes carry a poor prognosis for the patient. A more detailed understanding of the biochemistry of apoptosis and the ways in which it is disabled in tumors will likely reveal new transformation selective death triggers which stimulate cell death in ways independent of components like p53 and increase the therapeutic window of these drugs in the clinics.
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PMID:Apoptosis in tumorigenesis and cancer therapy. 923 63

During development, excess neurons are produced about half of which die. The time of cell death (apoptosis) is limited to the period of formation of synapses with the target cells, and the neurons which fail to obtain sufficient amounts of trophic factor(s) released from the target cells are eliminated. This selection system is considered to be a mechanism to ensure formation of a physiologically relevant neuronal network. Mature neurons which correctly execute their functions, however, undergo apoptosis in response to exogenous toxic stimuli. Such stimuli may be responsible for neurodegenerative diseases. The mechanism underlying cell death has been analyzed using in vitro model systems. In the present communication, we used cultured rat cerebellar granule neurons, in which low potassium concentration (LK+) in the medium induces apoptosis, and this apoptosis is prevented by high concentration of potassium (HK+), BDNF. One of the lipid-modifying kinases, phosphatidylinositol 3-kinase (PI3-K), is also activated by trophic factors including neurotrophins. BDNF and high K+ prevented low K(+)-induced apoptosis via PI3-K. BDNF also promotes the survival of basal forebrain cholinergic neurons cultured from postnatal 2-week-old (P2w) rats. The mechanism of neuronal apoptosis induced by oxidative stress using CNS neurons and PC12 cells was investigated, and we found that generation of reactive oxygen species (ROS) is highly associated with apoptosis. High oxygen induced neuronal apoptosis, which was blocked by protein or RNA synthesis inhibitors. Neurotrophic factors and Bcl-2 prevented this apoptotic cell death. Exposure to hydrogen peroxide, lipid hydroperoxide or serum deprivation triggered apoptosis associated with increased generation of ROS as determined using a ROS-specific fluorescent probe. In cultured cerebellar granule neurons from 15-day-old wild-type and p53-deficient mice, we examine the role of p53 in regulating the life and death of CNS neurons. When exposure of gamma-ray or bleomycin to neurons died in p53 dependent manner. These neuronal deaths were partially prevented by actinomycin D or cycloheximide. The pycnotic nuclei observed in these dying neurons indicated that cell death occurs via apoptosis. Although there are many evidences that p53 is involved in apoptosis in proliferating cells, it is interesting that p53 is also involved in apoptosis in postmitotic neurons as shown in this study.
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PMID:[Neuroprotection by neurotrophic factors in apoptosis]. 1019 Jan 24

Overexpressed MDM2 inactivates wild-type (wt) p53 in various human tumors. However, whether and how the wild-type p53 can be activated by anticancer drug treatment in the presence of excess MDM2 is still unclear. In the present study, we showed that the topoisomerase II inhibitor of widely used anticancer drugs etoposide and doxorubicin activated wt p53 in BL2, a Burkitt's lymphoma cell line which overexpressed MDM2. Activation of p53 was followed by apoptosis in BL2 cells, while the same drug treatment did not induce apoptosis in Raji cells, another Burkitt's lymphoma cell line which carried mutant p53. Activation of p53 was accompanied by phosphorylation of p53 at Ser-15 and elevated p21 and MDM2, both of which were at least partly blocked by wortmannin, a kinase inhibitor against proteins with a PI3 kinase domain. Although MDM2 protein was rapidly cleaved and degraded after anticancer drug treatment, cotreatment with caspase inhibitor Z-VAD blocked degradation, while wt p53 remained activated, suggesting MDM2 degradation not to be essential for the activation of p53. Treatment with proteasome inhibitor stabilized p53 without being further phosphorylated. This p53 was co-immunoprecipitated with MDM2, but p53 activated by etoposide or doxorubicin barely complexed with MDM2. These results suggest that the wild-type p53 in MDM2-overexpressing cells can be activated by anticancer drugs through phosphorylation of p53, alleviating inhibitory action by MDM2, and activating caspases which in turn downregulates MDM2. The activation of p53 in MDM2-overexpressing tumor cells, which does not require the downregulation of MDM2, may have important implications in cancer therapy.
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PMID:Activation of p53 in MDM2-overexpressing cells through phosphorylation. 1054 21

In this report, we examine how the Ras protein regulates neuronal survival, focusing on sympathetic neurons. Adenovirus-expressed constitutively activated Ras (RasV12) enhanced survival and the phosphorylation of Akt (protein kinase B) and MAP kinase (MAPK), two targets of Ras activity. Functional inhibition of endogenous Ras by adenovirus-expressed dominant-inhibitory Ras (N17Ras) decreased nerve growth factor (NGF)-dependent survival and both Akt and MAPK phosphorylation as well. To determine the signaling pathways through which Ras mediates survival, we used Ras effector mutants and pharmacological inhibitors that selectively suppress phosphatidylinositol 3-kinase (PI3-K)/Akt or MAP kinase kinase (MEK)/MAPK pathways. The Ras effector mutant Ras(V12)Y40C, which selectively stimulates PI3-K and Akt, rescued survival in the absence of NGF, and the PI3-K inhibitor LY 294002 inhibited both Ras- and NGF-dependent survival. Ras(V12)T(35)S, which activates MEK/MAPK but not PI3-K/Akt, was less effective at rescuing survival, whereas the MEK inhibitor PD 098059 also partially suppressed Ras-dependent survival. To investigate the mechanisms by which Ras suppresses neuronal death, we examined whether Ras functions by inhibiting the proapoptotic p53 pathway (Jun-N-terminal kinase/p53/BAX) that is necessary for neuronal death after NGF withdrawal and p75NTR activation. We found that RasV12 suppressed c-jun, BAX, and p53 levels, whereas inhibition of NGF-induced Ras-survival activity via N17Ras increased the levels of these proteins. Furthermore, the E1B55K protein, which suppresses p53 activity, blocked N17Ras-induced neuronal death. Together, these results indicate that Ras is, in part, both necessary and sufficient for survival of sympathetic neurons and that this effect is mediated by activation of both the PI3-K- and MEK-signaling cascades, which in turn suppress a proapoptotic p53 pathway.
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PMID:Ras regulates sympathetic neuron survival by suppressing the p53-mediated cell death pathway. 1055 81

Neurofibromatosis 1 (NF1) is a common autosomal dominant cancer predisposition syndrome, in which 15% to 20% of affected individuals develop astrocytomas. Neurofibromin, the protein product of the NF1 gene, functions as a tumor suppressor, largely by inhibiting Ras activity. While loss of neurofibromin has been implicated in the molecular pathogenesis of other NF1-associated tumors, there is no formal evidence demonstrating loss of neurofibromin function in NF1-associated astrocytomas. In this report, we describe an NF1 patient from whom both astrocytoma tumor tissue as well as corresponding non-neoplastic white matter were available for analysis. Loss of neurofibromin expression was observed in the tumor and was associated with elevated levels of Ras-GTP. However, elevated Ras-GTP levels were not the result of oncogenic Ras mutations, altered p120-GAP function, growth factor receptor activation, or abnormal p53, Rb, or p16 expression. Furthermore, increased Raf-MAPK and PI3-K/Akt activity was detected in the NF1 astrocytoma compared with the corresponding normal white matter. These results support a role for neurofibromin as the critical GAP in the molecular pathogenesis of NF1 astrocytomas.
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PMID:Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. 1100 56

Breast tumor cells are relatively refractory to apoptosis in response to modalities which induce DNA damage such as ionizing radiation and the topoisomerase II inhibitor, adriamycin. Various factors which may modulate the apoptotic response to DNA damage include the p53 status of the cell, levels and activity of the Bax and Bcl-2 families of proteins, activation of NF-kappa B, relative levels of insulin like growth factor and insulin-like growth factor binding proteins, activation of MAP kinases and PI3/Akt kinases, (the absence of) ceramide generation and the CD95 (APO1/Fas) signaling pathway. Prolonged growth arrest associated with replicative senescence may represent an alternative and reciprocal response to DNA-damage induced apoptosis that is p53 and/or p21waf1/cip1 dependent while delayed apoptosis may occur in p53 mutant breast tumor cells which fail to maintain the growth-arrested state. Clearly, the absence of an immediate apoptotic response to DNA damage does not eliminate other avenues leading to cell death and loss of self-renewal capacity in the breast tumor cell. Nevertheless, prolonged growth arrest (even if ultimately succeeded by apoptotic or necrotic cell death) could provide an opportunity for subpopulations of breast tumor cells to recover proliferative capacity and to develop resistance to subsequent clinical intervention.
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PMID:Growth arrest and cell death in the breast tumor cell in response to ionizing radiation and chemotherapeutic agents which induce DNA damage. 1107 87

v-Jun shares the ability of the Myc, E1A, and E2F oncogenes to both sustain cell cycle progression and promote apoptosis in the absence of mitogenic stimulation. To gain an insight into the mechanism of apoptosis sensitization, we examined the possible involvement of key regulatory proteins previously implicated in oncogene-induced cell death during v-Jun-induced apoptosis triggered by serum withdrawal. We observed that ectopic expression of the anti-apoptotic Bcl-2 protein, or of two downstream effectors of growth factor signalling, v-PI 3-Kinase and v-Src, partially or completely suppressed apoptosis. Apoptosis was also observed in the presence of serum growth factors when endogenous PI3K activity was blocked using the synthetic inhibitor LY294002, further suggesting an important role for PI3-K in cell survival. Cytochrome C was released into the cytosol of apoptotic v-Jun expressing cells, and this release was inhibited by Bcl-2, suggesting an important role for mitochondrial dysfunction in v-Jun induced apoptosis. In contrast, inhibition of Fas signalling using dominant negative FADD did not inhibit apoptosis, nor was there any evidence for accumulation or activation of p53 in v-Jun transformed cells. Consistent with this latter observation, inhibition of p53 function by HPV16 E6 protein had no effect on v-Jun induced cell death. Taken together, these results suggest that mitochondrial dysfunction is an important component of the mechanism through which v-Jun sensitizes cells to apoptosis, but that the apoptotic signals elicited by v-Jun upstream of the mitochondria do not depend on increased levels of p53 activity or Fas signalling.
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PMID:v-Jun sensitizes cells to apoptosis by a mechanism involving mitochondrial cytochrome C release. 1112 22

Ataxia-telangiectasia (AT) is an autosomally recessive human genetic disease with pleiotropic defects such as neurological degeneration, immunodeficiency, chromosomal instability, cancer susceptibility and premature aging. Cells derived from AT patients and ataxia-telangiectasia mutated (ATM)-deficient mice show slow growth in culture and premature senescence. ATM, which belongs to the PI3 kinase family along with DNA-PK, plays a major role in signaling the p53 response to DNA strand breaks. Telomere maintenance is perturbed in yeast strains lacking genes homologous to ATM and cells from patients with AT have short telomeres. We examined the length of individual telomeres in cells from ATM(-/-) mice by fluorescence in situ hybridization. Telomeres were extensively shortened in multiple tissues of ATM(-/-) mice. More than the expected number of telomere signals was observed in interphase nuclei of ATM(-/-) mouse fibroblasts. Signals corresponding to 5-25 kb of telomeric DNA that were not associated with chromosomes were also noticed in ATM(-/-) metaphase spreads. Extrachromosomal telomeric DNA was also detected in fibroblasts from AT patients and may represent fragmented telomeres or by-products of defective replication of telomeric DNA. These results suggest a role of ATM in telomere maintenance and replication, which may contribute to the poor growth of ATM(-/-) cells and increased tumor incidence in both AT patients and ATM(-/-) mice.
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PMID:Extra-chromosomal telomeric DNA in cells from Atm(-/-) mice and patients with ataxia-telangiectasia. 1118 76

PTEN tumor suppressor is frequently mutated in human cancers and is a negative regulator of PI3'K/PKB/Akt-dependent cellular survival. Investigation of the human genomic PTEN locus revealed a p53 binding element directly upstream of the PTEN gene. Deletion and mutation analyses showed that this element is necessary for inducible transactivation of PTEN by p53. A p53-independent element controlling constitutive expression of PTEN was also identified. In contrast to p53 mutant cell lines, induction of p53 in primary and tumor cell lines with wild-type p53 increased PTEN mRNA levels. PTEN was required for p53-mediated apoptosis in immortalized mouse embryonic fibroblasts. Our results reveal a unique role for p53 in regulation of cellular survival and an interesting connection in tumor suppressor signaling.
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PMID:Regulation of PTEN transcription by p53. 1154 34


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