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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BCL2 gene is the most representative member of a family of genes that control cell homeostatic processes in the course of the developmental and adult life. Some members of the BCL2 family (bcl-2 alpha, bcl-xL) inhibit apoptosis, whereas some other (Bax, Bclxs) induce it. The biological activity of these proteins is dictated by: 1) their capacity to be integrated in specific membranes of the cytoplasm; 2) their ability to homo- or hetero-dimerize, due to the presence of two highly conserved domains which are a signature of this gene family. The bcl-2 protein exhibits two main biochemical properties: it acts in an antioxidant metabolic pathway aimed at eliminating oxygene free radicals that induce lesions in DNA, lipids and proteins; it modulates intracellular Ca++ fluxes. BCL2 (and presumably its congeners) interplay with other genes involved in the tight control of cell proliferation and programmed cell death (c-myc, p53). A more comprehensive view of BCL2 functions should benefit to cancer chemotherapy by improving rational approach of the antitumor drug mechanisms.
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PMID:[The BCL2 gene, prototype of a gene family that controls programmed cell death (apoptosis)]. 784 93

The tumor suppressor p53 plays a central role in negative growth control, including growth arrest and apoptosis. Interferons (IFNs) are capable of modulating a variety of cellular responses, including apoptosis. In this study, we have evaluated the influence of gamma- and alpha-interferon (IFN) on wild-type (wt) p53-induced apoptosis using a Burkitt lymphoma cell line, BL41, transfected with a temperature-sensitive p53 construct, gamma-IFN, but not alpha-IFN, was found to protect cells from wt p53-induced apoptosis. The gamma-IFN-dependent protection was due neither to down-regulation of p53, nor to the p53-induced genes, p21 (WAF-1) and bax, nor to up-regulation of bcl-2 or bcl-xL. Expression of the proto-oncogene c-myc, implicated in the control of both proliferation and apoptosis, was not affected by gamma-IFN. We conclude that gamma-IFN can suppress p53-induced apoptosis, and that the cytokine microenvironment may be decisive in the cellular response to wt p53 expression.
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PMID:Wild-type p53-induced apoptosis in a Burkitt lymphoma cell line is inhibited by interferon gamma. 869 May 9

The disruption of cell cycle regulation is associated with developmental abnormalities and tumorigenesis. The SV40 large T antigen (Tag) interferes with cell cycle control by interacting with the pRb family and p53. Mice carrying a transgene composed of the whey acidic protein (WAP) gene promoter and the Tag coding sequence express Tag during pregnancy and are unable to nurse their young. Tag expression induced apoptosis in mammary epithelial cells during late pregnancy. At least 5% of mammary epithelial cells were undergoing apoptosis at any one time. In contrast, less than 0.2% of mammary epithelial cells in nontransgenic littermates was undergoing apoptosis. Apoptosis in Tag mice was associated with increased steady-state RNA levels of bax and bcl-xL + S, with a relative increase in bcl-xs expression. Since p53 was sequestered by Tag, it is likely that p53-independent mechanisms precipitated apoptosis. The Tag-expressing mammary alveolar cells that did not undergo apoptosis continued to differentiate through late pregnancy, as measured by the sequential activation of milk protein gene expression. However, milk protein production, processing, and secretion was impaired, resulting in lactation failure.
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PMID:Expression of a viral oncoprotein during mammary gland development alters cell fate and function: induction of p53-independent apoptosis is followed by impaired milk protein production in surviving cells. 878 28

Mammary gland involution is a physiological process that follows lactation and results in the rapid disappearance of the entire lobulo-alveolar compartment. Coincident with the onset of involution, milk protein gene expression ceases and alveolar cells undergo programmed cell death. In mammary epithelial tissue culture cells in vitro, both p53-dependent and p53-independent apoptosis pathways have been identified. We investigated whether p53 induces apoptosis during mammary gland involution in vivo and participates in tissue remodeling. Toward this end, we examined the process of involution in the presence and absence of functional p53 in mouse models: wild-type, transgenic mice that express SV40 T-antigen specifically in mammary tissue during pregnancy; and mice that carry nonfunctional p53 alleles in their germ line. Mammary gland whole-mount and histological analyses revealed that involution and remodeling, with the concomitant disappearance of the lobulo-alveolar structures, proceeded normally in the absence of functional p53. In addition, the absence of functional p53 did not alter the involution related pattern of bax (death inducer) gene expression or the ratio of RNAs encoding bcl-xs (death inducer) to bcl-xL (survival inducer).
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PMID:Apoptosis and remodeling of mammary gland tissue during involution proceeds through p53-independent pathways. 878 29

Mammary gland involution is a physiological process in which the entire organ is remodeled through the process of apoptosis. Apoptosis of secretory alveolar cells is initiated at the time of weaning, followed by the collapse and disappearance of the entire lobuloalveolar compartment. While apoptotic figures were rare in mammary epithelium of lactating mice, their number increased after weaning and reached a maximum on day 3 of involution. Active cell death continued until day 5 after weaning and only little parenchyma remained on day 8, when remodeling of the gland was completed. Bax mRNA levels increased during the first day of involution independent of the presence or absence of p53. Bax protein was detected in an increasing number of cells after weaning, peaking at day 3 and decreasing thereafter. Low levels of bcl-x mRNA and protein were present during lactation, followed by a sharp increase during the first 2 days of involution. The bcl-xS splice variant of bcl-x can promote cell death, and bcl-xL has a protective function in cell culture. The ratio of bcl-xS versus bcl-xL remained stable in the virgin, pregnant and lactating gland. However, during the first 2 days of involution, bcl-xS expression increased six-fold more than bcl-xL. To further evaluate the role of Bcl-xS which was less abundant in the mammary cells than Bcl-xL, cotransfection studies were performed in cell culture. They confirmed that Bcl-xS protein can facilitate apoptosis even when Bcl-xL is present in excess. These findings point to a significant role for Bax and Bcl-xS in the regulation of apoptosis of secretory alveolar cells during involution.
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PMID:Bax and Bcl-xs are induced at the onset of apoptosis in involuting mammary epithelial cells. 879 58

In a mouse model of multistage tumorigenesis of islet beta-cells, apoptosis was activated concomitant with T-antigen oncogene-induced cell proliferation, further increased in the angiogenic stage, and markedly reduced in solid tumors. Crosses to p53-null mice confirmed this stage-specific variation as a p53-independent apoptotic process. Several apoptosis regulators were expressed, of which bcl-xL was up-regulated in tumors. When overexpressed throughout the pathway, bcl-xL protected most oncogene-expressing cells from apoptosis, enhancing progression from angiogenic progenitor to tumor without affecting earlier transitions. Further, two classes of solid tumor are described, distinguished by size and apoptotic incidence, implicating apoptosis regulation in expansive tumor growth. Thus, down-modulation of apoptosis selectively contributes to late steps in a tumorigenesis pathway.
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PMID:The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. 880 6

To characterize the nature of programmed cell death (PCD) induced in neuronal cells during development, three regulators of apoptosis were investigated: one, the bcl-2-related genes, modulate cell survival, and the other two, the interleukin-1 beta converting enzyme (ICE)-related enzymes and the tumor suppressor protein p53, have been implicated as mediators of apoptosis. These regulators were studied in H19-7 cells, an SV40 Tts-immortalized rat hippocampal neuronal cell line that can be differentiated with basic fibroblast growth factor at the nonpermissive temperature, resulting in a rapid attrition of cells by apoptosis. PCD occurred by two mechanisms in H19-7 cells: The first was initiated by removal of serum from undifferentiated cells, and the second was a consequence of neuronal differentiation. In differentiated H19-7 cells, the survival time was increased by both human bcl-2 and bcl-xL, and this could be reversed by bcl-xs. Addition of a peptide inhibitor of the ICE enzyme family to H19-7 cells resulted in a transient protection against differentiation-associated apoptosis, whereas no further protection was observed in the BCL-2- or BCL-XL-expressing cells. Shifting the differentiated cells to 33 degrees C to inactivate p53 did not significantly affect the apoptotic process, indicating that apoptosis induced by neuronal differentiation is not dependent on the continued presence of p53. By contrast, in undifferentiated cells, cell loss induced by transfer to serum-free media occurred more rapidly on inactivation of large T, consistent with p53 involvement. This medium-induced decrease in cell survival could not be rescued by the ICE inhibitor but was partially rescued by BCL-2 or BCL-XL. Furthermore, studies involving expression of BCL-2 and BCL-XL alone or together revealed differences in the survival dependent on the cellular environment. These results suggest that apoptosis of neuronal cells occurs by at least two processes: one in undifferentiated cells initiated by removal of serum and one linked to differentiation. The data implicate the ICE enzyme family but not p53 in apoptosis induced by differentiation and demonstrate that either BCL-2 or BCL-XL can prolong the survival of differentiated neuronal cells.
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PMID:Apoptosis induced by differentiation or serum deprivation in an immortalized central nervous system neuronal cell line. 886 95

We have investigated the effect of DNA damage on the expression of BCL-X, a member of the BCL-2 family. BCL-X mRNA levels were found to increase upon exposure human cells to ionizing radiation (IR). The Bcl-X(L) protein, but not Bcl-X(S), was identified to be induced by IR. Like BAX, another member of the BCL-2 family and a p53-regulated gene, the induction of BCL-X(L) was dependent on normal p53 function and required that cells have an apoptosis-susceptible phenotype. The induction of BCL-X(L) was rapid, transient and dose-dependent. The mRNA level peaked at 4 h and returned to baseline by 24 h post-irradiation. In agreement with the increased transcript level, Bcl-X(L) protein level was also observed to increase in cells with wild-type p53 where IR triggered apoptosis. In addition, a survey of the BCL-X(L) mRNA basal levels in human cells with known apoptotic responses showed that low basal levels of BCL-X(L) mRNA in cells were highly correlated with a strong ability of cells to undergo IR-induced apoptosis. On the other hand, high levels of basal BCL-X(L) were correlated with the resistance of cells to IR-induced apoptosis regardless of p53 status. These results indicate that BCL-2 and BCL-X(L) behave differently in response to DNA damage treatment even though they both are able to protect cells from p53-mediated apoptosis; along with down-regulation of BCL-2, BCL-X(L) was up-regulated by IR in human cells with wild-type p53 and susceptibility to IR-induced apoptosis. We speculate that the physiological function of increased BCL-X(L) protein would be expected to probably limit the severity and length of BAX effect in order to maintain a proper threshold for apoptosis and to complete cell cycle arrest activated by p53.
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PMID:The apoptosis-associated gamma-ray response of BCL-X(L) depends on normal p53 function. 895 Sep 97

The Apo-1/Fas (CD95) antigen is known to be involved in the process of T cell-mediated target cell killing and has recently been shown to be expressed on myeloma cell lines and native malignant plasma cells. Several cytokines have been reported to interfere with spontaneous and even Apo-1/Fas-induced apoptosis, but no attempt has been made yet to investigate these interactions and the possible underlying mechanisms in myeloma cells. Since in myeloma patients Interferon (IFN)-alpha2 displays a profound therapeutic effect in vivo, which is usually attributed to its growth inhibitory and/or immunomodulatory capacity, we set out to study the potential interference of IFN-alpha2 with Apo-1/Fas-induced apoptosis. Contrary to expectations, IFN-alpha2 reduced the degree of apoptosis caused by the treatment of five Apo-1/Fas-sensitive myeloma cell lines with a Fas monoclonal antibody (mAb). Simultaneous application of IFN-alpha2 and Fas mAb was superior to the prolonged (i.e. >8 h) preincubation with the cytokine as far as inhibition of Apo-1/Fas-induced apoptosis was concerned. This effect of IFN-alpha2 was neither explained by a down-regulation of the Apo-1/Fas receptor nor caused by modulation of the expression levels of c-myc, bcl-2-, bcl-xL, bax- or p53 genes. IFN-alpha2 did not alter the Apo-1/Fas-induced activity of Mitogen-activated protein kinase (MAPK) 1 and did not inhibit the Apo-1/Fas-mediated proteolytic cleavage of ADP-ribosyltransferase, a substrate of Interleukin-beta1 converting enzyme (ICE) and homologues. However, activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) mimicked the effects of IFN-alpha2. Furthermore, the bis-indolylmaleimide GF 109203X, a specific inhibitor of PKC, inhibited the effect of PMA as well as that of IFN-alpha2 on Apo-1/Fas-induced apoptosis. These results point to a PKC-dependent mechanism of transient interaction between the intracellular signaling along the IFN-alpha2 and the Apo-1/Fas pathway (downstream of MAPK signaling as well as of ICE homologues), which becomes exhausted by prolonged stimulation with the cytokine. According to our data IFN-alpha2, applied continuously and in high doses resembling the therapeutic situation in vivo, inhibits myeloma growth. However, based on the observed inhibitory effect of IFN-alpha2 on Apo-1/Fas-induced apoptosis, a partial inhibition of the natural immune surveillance on myeloma cells by endogenous IFN-alpha2 present in the bone marrow microenvironment of this malignancy should be investigated.
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PMID:Modulation of Apo-1/Fas (CD95)-induced programmed cell death in myeloma cells by interferon-alpha 2. 897 13

Of six prostatic carcinoma cell lines examined (ALVA31, DU145, JCA1, LNCaP, ND1, and PC3) by flow cytometric analysis, all were found to be positive for Fas antigen. Furthermore, of the prostate tissue specimens studied (six cases), all revealed Fas expression in benign and malignant epithelial cells. The agonistic anti-Fas monoclonal antibody (IPO-4) induced apoptosis in only two of six cell lines investigated, PC3 and ALVA31. PCR analysis indicated that all cell lines expressed normal transmembrane and death domains of Fas antigen. Using Western blot analysis, we found abundant expression of p53 in the cytoplasm of two Fas-resistant cell lines, DU145 and ND1, and did not find p53 in two Fas-sensitive cell lines, PC3 and ALVA31. Western blot and PCR analysis did not show consistent differences between cell lines examined in the expression of Bcl-2, Bcl-X(L), Bcl-X(S), and Bak. In contrast, Bax protein was not detected in two Fas-resistant cell lines, DU145 and ND1. We also showed that three Fas-resistant cell lines, DU145, ND1, and JCA1, expressed CD40, whereas the two Fas-sensitive cell lines, PC3 and ALVA31, were CD40 negative. Fas-sensitive cell lines were transfected with the cDNA encoding CD40, and the CD40-positive transfectant became more resistant to growth inhibition mediated by treatment with TNF-alpha and anti-Fas monoclonal antibody. Treatment with cycloheximide converted the phenotype of resistant cell lines from Fas resistant to Fas sensitive. Moreover, anti-Fas treatment of both resistant and sensitive cell lines induced rapid tyrosine phosphorylation or dephosphorylation of multiple proteins. These results suggest that the apoptotic machinery involved in DNA fragmentation is already in place in Fas-resistant cell lines, and thus, Fas-mediated apoptosis could be a target for therapeutic intervention.
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PMID:Fas-mediated apoptosis in human prostatic carcinoma cell lines. 913 20


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