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)

We describe the properties of a physiological cell death (PCD)-resistant subline of WEHI-231 generated from the PCD-susceptible WEHI-231.7 JM cell line maintained in our laboratory. The PCD-resistant WEHI-231.7 JMRE subline was uniquely resistant to anti-immunoglobulin (Ig)M-induced PCD but not to irradiation and etoposide. In these sublines, we compared the expression of genes implicated in regulating PCD. Northern analysis of c-myc, c-fos, egr-1, Fas, p53 and retinoblastoma revealed similar basal levels of expression in all sublines tested and comparable responses to anti-IgM treatment. Similarly, the expression of bcl-2, bcl-x, bax and IL-1 beta converting enzyme did not correlate with susceptibility to anti-IgM-induced PCD. Next, we systematically studied signal transduction events including: tyrosine phosphorylation, Ca++ flux, and ceramide production in the Jm and JMRE sublines. The tyrosine phosphorylation patterns and the Ca++ influx generated following sIgM engagement were very similar in the JM and JMRE sublines. In contrast, the generation of ceramide differed in the PCD-resistant and PCD-susceptible sublines. Ceramide is produced following cross-linking sIgM on WEHI-231.7 JM cells and causes PCD. Ceramide levels in anti-IgM-treated WEHI-231.7 JMRE cells are low and appear to be insufficient to induce PCD.
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PMID:Resistance to anti-IgM-induced apoptosis in a WEHI-231 subline is due to insufficient production of ceramide. 753 68

This review attempts to provide current information on the role played by the p53 gene in normal and leukemic hematopoiesis with particular emphasis on chronic myeloid leukemia. On the basis of the currently available data we can argue that p53 acts as a negative regulator of proliferation of myeloid mature cells and CD34+ progenitors, and its action is mediated through changes in cell cycle kinetics, mainly before the S phase. The p53-dependent pathway is also regulated by several proteins, including p16, p21, p27 (cyclin-dependent kinase [CDK] inhibitors), and a few oncogenes (bcl-2, bax, MDM-2). Although there is some information about the changes in the p53 gene seen in various types of leukemia, the functions and biological importance of these changes in the pathogenesis of leukemia are still largely elusive. During the past several years, accumulated evidence suggests that changes in the p53 gene are commonly associated with blast crisis of chronic myeloid leukemia (CML) but rarely with chronic phase, and they are represented by rearrangements, deletions and point mutations. As for most of the tumors, the majority of point mutations occur between exons 4 and 8 (hot regions). In patients with CML in blastic crisis the most frequent mechanism of p53 inactivation is complete deletion of one allele in association with a point mutation in the remaining allele.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of p53 in leukemogenesis of chronic myeloid leukemia. 754 4

The p53 tumor suppressor gene is thought to be required for the induction of programmed cell death (apoptosis) initiated by DNA damage. We show here, however, that the human promyelocytic leukemia cell line HL-60, which is known to be deficient in p53 because of large deletions in the p53 gene, can be induced to undergo apoptosis following X-irradiation. We demonstrate that the decision to undergo apoptosis in this cell line appears to be made at a G2 checkpoint. In addition, we characterize an HL-60 variant, HCW-2, which is radioresistant. HCW-2 cells display DNA damage induction and repair capabilities identical to those of the parental HL-60 cell line. Thus, the difference between the two cell lines appears to be that X-irradiation induces apoptosis in HL-60, but not in HCW-2, cells. Paradoxically, HCW-2 cells display high levels of expression of bax, which enhances apoptosis, and no longer express bcl-2, which blocks apoptosis. HCW-2 cells' resistance to apoptosis may be due to the acquisition of expression of bcl-XL, a bcl-2-related inhibitor of apoptosis. In summary, apoptosis can be induced in X-irradiated HL-60 cells by a p53-independent mechanism at a G2 checkpoint, despite the presence of endogenous bcl-2. The resistance shown by HCW-2 cells suggests that bcl-XL can block this process.
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PMID:Evidence for a G2 checkpoint in p53-independent apoptosis induction by X-irradiation. 756 37

Transcriptional activation of target genes represents an important component of the tumour-suppressor function of p53 and provides a functional link between p53 and various growth-regulatory processes, including cell cycle progression (p21/WAF1), DNA repair (GADD45) and apoptosis (bax). Here we use a differential cloning approach to identify the gene encoding insulin-like growth factor binding protein 3 (IGF-BP3) as a novel p53-regulated target gene. Induction of IGF-BP3 gene expression by wild-type but not mutant p53 is associated with enhanced secretion of an active form of IGF-BP3 capable of inhibiting mitogenic signalling by the insulin-like growth factor IGF-1. Our results indicate that IGF-BP3 may link p53 to potential novel autocrine/paracrine signalling pathways and to processes regulated by or dependent on IGF(s), such as cellular growth, transformation and survival.
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PMID:Induction of the growth inhibitor IGF-binding protein 3 by p53. 756 79

The biological activity of a novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (AHPN) was investigated in human breast carcinoma (HBC) cells. Although capable of selective binding to the RAR gamma nuclear receptor, AHPN inhibited the growth of a number of HBC cell lines via RAR- or RXR-independent pathways. AHPN also inhibited the growth of the human leukemia cell line HL-60R which does not possess functional RARs. RA significantly inhibited AP-1 mediated gene activation in MCF-7 cells while AHPN displayed no such anti-AP-1 activity. Retinoids normally are cytostatic in their inhibition of breast carcinoma growth and permit cell proliferation upon their removal, wher as AHPN induced G0/G1 arrest within 6h followed by apoptosis. In MCF-7 cells that harbor wild type p53, AHPN-induced G0/G1 arrest and apoptosis was accompanied by p53-independent regulation of WAF1/CIP1 as well as bax mRNA levels while bcl-2 mRNA levels were decreased. In MDA-MB-231 cells which possess a mutant p53, AHPN-mediated G0/G1 arrest and apoptosis was also associated with a concomitant up regulation of WAF1/CIP1 mRNA while these cells did not express bax or bcl-2 messages. Thus AHPN represents a novel retinoid that induces G0/G1 arrest and apoptosis via a unique pathway which appears to involve activation of known downstream effectors of p53 in a p53-independent manner.
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PMID:p53 independent G0/G1 arrest and apoptosis induced by a novel retinoid in human breast cancer cells. 763 Jun 33

Systemic administration of kainate induces cell death in vulnerable regions of the rodent brain. Neuronal degeneration is associated with internucleosomal DNA fragmentation and induction of presumptive cell death effector genes (e.g. p53, c-fos) suggesting that kainate activates an apoptotic pathway. In the present study, kainate-induced DNA damage has been demonstrated at the cellular level by in situ nick translation in the mouse hippocampus and neocortex at 24 h and 48 h after intraperitoneal injections. In the same regions, the intensity of Bcl-2 immunoreactivity decreased by about 45% as measured by digital image analysis. Most important, kainate treatment evoked a nearly 3-fold increase in bax mRNA levels within the mouse brain. The down-regulation of bcl-2, which promotes cell survival, and the up-regulation of bax, which promotes programmed cell death, may have functional significance in kainate-mediated excitotoxicity and in the selective vulnerability of specific brain regions.
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PMID:Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain. 767 27

The p53 protein is a transcription regulator that is frequently altered by mutation in cancer. Breakthroughs on two fronts shed light on its role in tumor suppression. First, a flurry of biochemical and structural studies (including a partial crystal structure) has sharpened the picture of p53 topology and functional properties. Second, downstream effectors of p53 have been identified including p21Waf-1/Cip-1, an inhibitor of cyclin-dependent kinases, and bax, a dominant-negative inhibitor of bcl-2. This suggest a scenario in which p53 is activated by genotoxic stress and regulates the transcription of at least two sets of genes. One is responsible for transient cell arrest in G1 and the other controls the initiation of apoptosis. Both processes eliminate potential oncogenic mutations, either by proper DNA repair or by inducing damaged cells to commit suicide.
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PMID:The tumor suppressor protein p53: a receptor to genotoxic stress that controls cell growth and survival. 769 67

Employing the myeloblastic leukemia M1 cell line, which does not express endogenous p53, and genetically engineered variants, it was recently shown that activation of p53, using a p53 temperature-sensitive mutant transgene (p53ts), resulted in rapid apoptosis that was delayed by high level ectopic expression of bcl-2. In this report, advantage has been taken of these M1 variants to investigate the relationship between p53-mediated G1 arrest and apoptosis. Flow cytometric cell cycle analysis has provided evidence that activation of wild-type (wt) p53 function in M1 cells resulted in the induction of G1 growth arrest; this was clearly seen in the M1p53/bcl-2 cells because of the delay in apoptosis that unmasked p53-induced G1 growth arrest. This finding was further corroborated at the molecular level by analysis of the expression and function of key cell cycle regulatory genes in M1p53 versus M1p53/bcl-2 cells after the activation of wt p53 function; events that take place at early times during the p53-induced G1 arrest occur in both the M1p53 and the M1p53/bcl-2 cells, whereas later events occur only in the M1p53/bcl-2 cells, which undergo delayed apoptosis, thereby allowing the cells to complete G1 arrest. Finally, it was observed that a spectrum of p53 target genes implicated in p53-induced growth suppression and apoptosis were similarly regulated, either induced (gadd45, waf1, mdm2, and bax) or suppressed (c-myc and bcl-2), after activation of wt p53 function in M1p53 and M1p53/bcl-2 cells. Taken together, these findings show that wt p53 can simultaneously induce the genetic programs of both G1 growth arrest and apoptosis within the same cell type, in which the genetic program of cell death can proceed in either G1-arrested (M1p53/bcl-2) or cycling (M1p53) cells. These findings increase our understanding of the functions of p53 as a tumor suppressor and how alterations in these functions could contribute to malignancy.
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PMID:Dissection of the genetic programs of p53-mediated G1 growth arrest and apoptosis: blocking p53-induced apoptosis unmasks G1 arrest. 774 28

The bax gene promoter region contains four motifs with homology to consensus p53-binding sites. In cotransfection assays using p53-deficient tumor cell lines, wild-type but not mutant p53 expression plasmids transactivated a reporter gene plasmid that utilized the bax gene promoter to drive transcription of chloramphenicol acetyltransferase. In addition, wild-type p53 transactivated reporter gene constructs containing a heterologous minimal promoter and a 39-bp region from the bax gene promoter in which the p53-binding site consensus sequences reside. Introduction of mutations into the consensus p53-binding site sequences abolished p53 responsiveness of reporter gene plasmids. Wild-type but not mutant p53 protein bound to oligonucleotides corresponding to this region of the bax promoter, based on gel retardation assays. Taken together, the results suggest that bax is a p53 primary-response gene, presumably involved in a p53-regulated pathway for induction of apoptosis.
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PMID:Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. 783 49

We have previously demonstrated that the gonadotropin-mediated inhibition of apoptosis in ovarian granulosa cells is linked to changes in the expression of several cell death-related genes, including members of the bcl-2 gene family (bcl-2, bax, and bcl-x). Recently, the product of the p53 tumor suppressor gene, a protein reported to play a critical role in regulating cell proliferation and death, has been shown to directly modulate the transcriptional activity of the bcl-2 and bax genes. In addition, the actions of p53 may be amplified through a cooperative interaction with another tumor suppressor protein, the product of the Wilms' tumor suppressor gene (WT-1). Based on our identification of a potential role for bcl-2-related factors in regulating granulosa cell apoptosis and the reported function of p53 as a regulator of bcl-2 and bax gene transcription in extragonadal cells, the present studies were conducted to determine whether the p53 and WT-1 genes are expressed and gonadotropin regulated in the rat ovary and to investigate whether granulosa cell apoptosis is linked to elevated levels of tumor suppressor gene expression. Northern blot analysis of total RNA prepared from immature (27-day-old) rat ovaries revealed the presence of a single p53 messenger RNA (mRNA) transcript (2.0 kilobases) and multiple WT-1 messages (1.8, 3.5, and 7.5 kilobases). Subcutaneous injection of immature rats with 10 IU equine CG (eCG) reduced the levels of p53 and WT-1 mRNA to 71 +/- 9% (P < 0.05) and 46 +/- 3% (P < 0.05), respectively, of saline-treated control levels after 2 days. The inhibition of tumor suppressor gene expression by eCG treatment was associated with a marked reduction in the number of apoptotic granulosa cells and atretic follicles. Furthermore, immunohistochemical analysis revealed that p53 protein was localized exclusively to nuclei of apoptotic granulosa cells of atretic follicles, and that p53 immunostaining was reduced to undetectable levels after in vivo treatment with eCG. To further evaluate whether granulosa cell apoptosis is linked to increased expression of tumor suppressor genes, we analyzed levels of p53 and WT-1 mRNA in antral follicles induced to undergo atresia in vitro by serum-free culture.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Expression of the p53 and Wilms' tumor suppressor genes in the rat ovary: gonadotropin repression in vivo and immunohistochemical localization of nuclear p53 protein to apoptotic granulosa cells of atretic follicles. 789 50


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