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

Protein phosphorylation has evolved as the most versatile posttranslational modification widely used by cells. Signal transduction pathways mediated by activation of MAP kinases and protein kinase C trigger the exit of cells from the quiscence (Go-->G1 transition). Indeed, binding of growth factors at the cell surface triggers their receptors, usually possessing a tyrosine kinase on the cytoplasmic side, to phosphorylate other molecules passing on the information sequentially to GRB2 protein, to p21ras, to c-Raf-1, to MAP kinase kinase, to MAP kinase, to p90rsk, to transcription factors. Activated PKC, MAP kinase, and pp90src can translocate to the nucleus where they phosphorylate a number of protein transcription regulators in a cell cycle-dependent manner or in response to cell stimulation for exit from quiescence. The cell cycle is mainly regulated by p34cdc2 or otherwise called cdc2 in association with cyclins B at G2/M and by Cdk2 in association with cyclins A, D1, and E at G1/S checkpoints; phosphorylation of histone H1 and lamins by cdc2 triggers chromosome assembly and nuclear envelope breakdown, respectively, as a prelude to mitosis. Cdc2 activities functioning as a G2/M regulator are controlled by its phosphorylation and dephosphorylation at Ser/Thr residues. MAP kinases might be the missing link in the chain connecting the Go to G1 transition with the cell cycle regulation, whereas phosphorylation of replication protein factors, retinoblastoma, and p53 might link the G1 to S transition with the control of DNA synthesis. A number of transcription factors are known to stimulate DNA replication, including p53, c-Myc, AP-1, Oct-1, T-antigen; the DNA binding activities of all these proteins and their interaction with other transcription factors are controlled by phosphorylation. The nuclear import of several proteins including NF kappa B, Dorsal, glucocorticoid receptor, ISGF3, rNFIL-6, T antigen, and the kinases PKC, MAP, and p90rsk, are dependent on their phosphorylation at specific sites. Histone phosphorylation stimulated at discrete stages of the cell cycle or in response to cAMP or other stimuli might induce profound changes in chromatin organization.
 ...
PMID:Phosphorylation of transcription factors and control of the cell cycle. 754 80

In the accompanying paper we described the induction of apoptosis by extended cyclic AMP (cAMP)-mediated signals in primary granulosa cells and the reduction in this process in transformed cells expressing SV40 T antigen. In the present work, we examined the effect of overexpression of either wild-type or mutant p53 on cAMP-mediated apoptosis in steroidogenic granulosa cell lines transfected with SV40 DNA together with the Ha-ras oncogene and a temperature-sensitive variant of p53, p53val135. In cell lines expressing low amounts of T antigen and high amounts of p53val135, growth arrest was induced by transferring the cells from 37.5 degrees to 32 degrees C, a temperature which allows the manifestation of the wild-type phenotype of p53 and the induction of the WAF1 gene. While nonstimulated cells showed only a very modest apoptotic process, rapid and massive apoptosis was evident in cells stimulated by forskolin at 32 degrees C. The presence of serum could delay, but not abolish, this phenomenon. Progesterone production in such cells treated with cAMP was significantly higher at 32 degrees C than at 37.5 degrees C, suggesting that wild-type p53 can also enhance granulosa cell differentiation. Furthermore, at least at early stages, apoptosis is correlated with increased cell differentiation. On the other hand, in lines expressing high amounts of T antigen and low amounts of p53, neither an increase in cAMP-induced differentiation nor massive apoptosis was seen at 32 degrees C. These findings demonstrate that wild-type p53 can cooperate with cAMP-generated signals in the induction of steroidogenesis and of programmed cell death in granulosa cells.
 ...
PMID:Involvement of p53 expression in cAMP-mediated apoptosis in immortalized granulosa cells. 773 66

Protein phosphorylation is a versatile posttranslational modification and the most eminent molecular mechanism that can regulate enzymatic activities, emergence of cells from quiescence, DNA replication and onset of mitosis, gene expression, nuclear import, development, and memory. The cell cycle is mainly regulated by p34cdc2 in association with cyclins B at G2/M and by Cdk2 in association with cyclins A, D1, and E at G1/S checkpoints. MAP kinases might link the G0 to G1 transition with the regulation of the cell cycle whereas phosphorylation of replication protein factors, c-Myc, AP-1, Oct-1, T-antigen, retinoblastoma, and p53 might link the G1 to S transition with the control of DNA synthesis. These transcription regulators can up- or downregulate DNA replication and their DNA binding activities or transacting properties are controlled by phosphorylation.
 ...
PMID:Control of DNA replication by protein phosphorylation. 787 68

RFLPs were detected in the five subunit genes of the human muscle nicotinic acetylcholine receptor (nAChR) using genomic DNA or cDNA probes from the homologous mouse loci. The RFLPs at the alpha-, beta-, gamma-, delta-, and epsilon-subunit gene loci were analyzed for genetic linkage in 16 families (n = 188). Significant evidence was obtained for close linkage of the beta- and epsilon-nAChR genes and much greater genetic distance between the alpha-nAChR gene and the gamma/delta-nAChR gene complex. The linkage analysis program CRI-MAP was used to map the positions of the beta- and epsilon-nAChR genes relative to seven markers on chromosome 17. The results indicate the beta- and epsilon-nAChR genes are separated by about 5 cM and located in the region of chromosome 17p occupied by D17S1, D17S31, TP53, and D17S513. The statistical evidence was confirmed by hybridization of the beta- and epsilon-nAChR probes to a panel of human-hamster somatic cell hybrids. The alpha-, gamma-, and delta-nAChR genes were placed on a map of 13 chromosome 2 markers. The linkage analysis placed the nAChR genes at two sites on chromosome 2q about equidistant from the marker CRYGP1, with the alpha-nAChR gene about 27 cM proximal and the gamma/delta-nAChR gene complex about 31 cM distal to CRYGP1.
 ...
PMID:Five subunit genes of the human muscle nicotinic acetylcholine receptor are mapped to two linkage groups on chromosomes 2 and 17. 790 25

Cellular senescence is a state of irreversible cell cycle arrest in which normal cells at the end of their lifespan fail to enter into DNA synthesis upon serum or growth factor stimulation. We examined whether proteins required for G1/S cell cycle progression were irreversibly down-regulated in senescent human fibroblasts. Both the 44- and 42-kDa forms of the MAP-kinase protein were expressed at similar levels in young and senescent cells. In contrast to young cells where both forms were phosphorylated on tyrosine in response to serum, the p42MAP-kinase was not tyrosine phosphorylated upon serum stimulation, whereas p44MAP-kinase was phosphorylated on tyrosine in serum-starved or serum-stimulated senescent cells. Examination of p53 protein in growing, quiescent, and senescent cells revealed no significant differences in levels between the different growth states. In contrast, cdk2 and cyclin A mRNAs were completely down-regulated in stimulated senescent fibroblasts, while the G1 cyclins, C, D1, and E mRNAs, were still expressed in stimulated senescent cells although at reduced levels compared to young cells. The expression of early G1 markers, but not late G1 markers, indicates that senescent cells may be blocked at a point in late G1. We investigated whether transfection of cyclin A, alone or in combination with cdc2, was sufficient for extension of lifespan or escape from senescence. Clones expressing the transfected human cyclin A or cdc2 genes senesced at a population doubling similar to controls, thereby showing that cyclin A or cdc2 expression alone was insufficient for escape from senescence.
 ...
PMID:Investigation of the role of G1/S cell cycle mediators in cellular senescence. 826 40

Paraffin-embedded materials obtained from 117 cases of endometrial hyperplasia and 84 cases of carcinoma were used for measurement of both ki-ras and p53 gene mutation and aromatase (ARO) and TGF-alpha immunostaining. The overall incidence of ki-ras mutations in the hyperplasia specimens (16%) was similar to the incidence detected in carcinomas (18%). None of 117 endometrial hyperplasias were found to have mutations in the p53 gene, whereas mutations were seen in 3 (13.3%) endometrial carcinomas. The intensity of both ARO and TGF-alpha immunostaining was increased in glands of both hyperplasia and carcinoma, and also in the interstitium of carcinoma. The positive sites of both ARO and TGF-alpha were almost the same, with an incidence below 40% in both hyperplasias and carcinomas. The cultured cells of endometrial carcinoma showed aromatase activity below MCF-7 cells, because testosterone was converted to estradiol (E2). TGF-alpha induced cell growth with at an optimal concentration. In HEC-59 cells, TGF-alpha increased both ARO-activity and mRNA. Some promoters on ARO-exon 1 in HEC-59 cells were different from those in BeWo cells. Progesterone inhibited the E2-induced excretion of pre TGF-alpha in endometrial carcinoma cells. These findings suggest that endometrial hyperplasia can be a premalignant condition of carcinoma, and can be initiated by both ki-ras codon 12 mutation and abnormal activity of ARO induced by TGF-alpha. In addition, HEC-59 cells may possess autocrine/paracrine properties involving ARO, E2 and TGF-alpha.
 ...
PMID:[Aromatase activities of endometrial carcinomas and both basic and clinical analyses of endometrial hyperplasia as a premalignant disease]. 837 Oct 7

Recently, much progress has been made in defining the signal transduction pathways mediating the cellular response to genotoxic stress. Multiple pathways involving several distinct MAP kinases (ERK, JNK/SAPK, and p38/HOG1) as well as the tumor suppressor protein p53 contribute to the response; the various pathways being differentially activated by particular genotoxic agents. Although both DNA damage and extranuclear events are important in initiating the response, recent evidence suggests the response is controlled primarily through events occurring at the plasma membrane, overlapping significantly with those important in initiating mitogenic responses. Attenuation of the responses appears to be largely controlled through feedback mechanisms involving gene products produced during the activation process.
 ...
PMID:Signaling events controlling the molecular response to genotoxic stress. 885 80

The two types of endometrial carcinomas are preceded by precancerous lesions. Type I endometrial carcinomas are most commonly encountered in perimenopausal women with the classical risk factors associated with estrogen exposure: obesity, multiparity, diabetes, estrogen treatment, ... Hyperplasia (simple, followed by complex forms without cellular atypias and subsequently by complex hyperplasias with cellular transformation) precede such cancers. Estrogens exert a promoting effect on these lesions but do not initiate them. Progesterone and progestins exert a preventive and protective effect. However, the progressive loss of steroidal receptors is correlated to the progression of tissular anomalies and to the onset of cytogenetic anomalies and to mutations of p53 anti-oncogene. The preventive role of progestin is well established, but their curative beneficial effect on atypical precursors forms of endometrial cancers and on endometrial carcinomas remains controversial. The second type of endometrial cancer appears during the postmenopause and is characterized by an increased invasiveness and a poor prognosis, devoid of identifiable risks factors, these aggressive cancers are not preceded by hormone-sensitive precancerous lesions, but by an intra-epithelial endometrial carcinoma. This lesion appears most often in an atrophic endometrium. Finally, the two types of precancerous states are characterized by distinct gene anomalies suggesting two different pathogenic mechanisms of cancerisation.
 ...
PMID:[Precancerous states of the endometrium: hormonal aspects]. 952 83

The organochlorine pesticide heptachlor constitutes a potential health hazard because of its persistence in nature, its reported contamination in food and milk, and its possible carcinogenic effects. As a tumor promoter, heptachlor induces human myeloblastic leukemia cells to differentiate, and also down-regulates the tumor suppressor gene p53 in human immune cells. In this study, the heptachlor signaling pathway in human lymphocytes was studied. Addition of heptachlor to human CEM x174 lymphocytic cells reduced the cellular levels of MAP kinase (MAPK, mitogen-activated protein kinase) cascade proteins, including ERK1 (a 44-kDa MAPK), ERK2 (a 42-kDa MAPK), a 85-kDa and a 54-kDa MAP kinase, MEK1 (a 45-kDa ERK kinase) and MEKK (a 78-kDa MEK kinase). However, heptachlor treatment caused a marked increase in the expression of the activated (Thr- and Tyr-dually phosphorylated) ERK1 and ERK2 in the cells. These studies indicate that mitogen-activated protein kinases are important intermediates in the signal transduction pathway of immune cells upon heptachlor exposure, and the observation of stimulation of activated MAP kinases without a simultaneous accumulation of basal enzymes may suggest the involvement of a negative feedback control mechanism in the pathway.
 ...
PMID:Heptachlor and the mitogen-activated protein kinase module in human lymphocytes. 970 2

Progesterone inhibits the proliferation of normal breast epithelial cells in vivo, as well as breast cancer cells in vitro. But the biologic mechanism of this inhibition remains to be determined. We explored the possibility that an antiproliferative activity of progesterone in breast cancer cell lines is due to its ability to induce apoptosis. Since p53 and bcl-2 genetically control the apoptotic process, we investigated whether or not these genes could be involved in the progesterone-induced apoptosis. We found a maximal 90 percent inhibition of cell proliferation with T47-D breast cancer cells after exposure to 10 microM progesterone for 72 hours. Control progesterone receptor negative MDA-231 cancer cells were unresponsive to these two concentrations of progesterone. After 24 hours of exposure to 10 microM progesterone, cytofluorometric analysis of T47-D breast cancer cells demonstrated 43 percent had undergone apoptosis without signs of necrosis. After 72 hours of exposure to 10 microM progesterone, 48 percent of the cells had undergone apoptosis and 40 percent demonstrated "leaky" membranes. Untreated cancer cells did not undergo apoptosis. Evidence proving apoptosis was also demonstrated by fragmentation of nuclear DNA into multiples of oligonucleosomal fragments. After 24 hours of exposure to either 1 microM or 10 microM progesterone, the expression by T47-D cancer cells of bcl-2 was down-regulated, and that of p53 was up-regulated as detected by semiquantitative RT-PCR analysis. These results demonstrate that progesterone at a concentration similar to that seen during the third trimester of pregnancy exhibited a strong antiproliferative effect on at least two breast cancer cell lines. Apoptosis was induced in the progesterone receptor expressing T47-D breast cancer cells.
 ...
PMID:Progesterone inhibits growth and induces apoptosis in breast cancer cells: inverse effects on Bcl-2 and p53. 984 3


1 2 3 4 5 6 7 8 9 10 Next >>