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)

Inactivation of the retinoblastoma (Rb) tumor suppressor in the mouse induces mid-gestational death accompanied by massive apoptosis in certain tissues. Herein, we analyzed the role of the apoptosis protease-activating factor Apaf-1, an essential component of the apoptosome, in mediating apoptosis in Rb-deficient mice. Analysis of compound mutant embryos lacking Rb and Apaf-1 revealed that Apaf-1 was absolutely required for apoptosis in the central nervous system and lens. In contrast, apoptosis in the peripheral nervous system and skeletal muscles only partly depended on Apaf-1 function. The dependency on Apaf-1 coincided with the requirement documented previously for E2F1 and p53 in the respective tissues. Loss of Apaf-1 specifically suppressed apoptosis but not the proliferation and differentiation defects in Rb-mutant embryos. We also show that the Apaf1+ but not the Rb+ allele is retained in pituitary tumors arising in Rb+/-:Apaf1+/- double heterozygous mice. Our results indicate that Apaf-1 plays a critical role in apoptosis in a subset of tissues and that both E2F1:p53:Apaf-1-dependent and -independent apoptotic pathways operate downstream of Rb.
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PMID:Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis. 1173 16

The breast cancer susceptibility gene BRCA1 encodes a protein that has been implicated in multiple nuclear functions, including transcription and DNA repair. The multifunctional nature of BRCA1 has raised the possibility that the polypeptide may regulate various nuclear processes via a common underlying mechanism such as chromatin remodeling. However, to date, no direct evidence exists in mammalian cells for BRCA1-mediated changes in either local or large-scale chromatin structure. Here we show that targeting BRCA1 to an amplified, lac operator-containing chromosome region in the mammalian genome results in large-scale chromatin decondensation. This unfolding activity is independently conferred by three subdomains within the transactivation domain of BRCA1, namely activation domain 1, and the two BRCA1 COOH terminus (BRCT) repeats. In addition, we demonstrate a similar chromatin unfolding activity associated with the transactivation domains of E2F1 and tumor suppressor p53. However, unlike E2F1 and p53, BRCT-mediated chromatin unfolding is not accompanied by histone hyperacetylation. Cancer-predisposing mutations of BRCA1 display an allele-specific effect on chromatin unfolding: 5' mutations that result in gross truncation of the protein abolish the chromatin unfolding activity, whereas those in the 3' region of the gene markedly enhance this activity. A novel cofactor of BRCA1 (COBRA1) is recruited to the chromosome site by the first BRCT repeat of BRCA1, and is itself sufficient to induce chromatin unfolding. BRCA1 mutations that enhance chromatin unfolding also increase its affinity for, and recruitment of, COBRA1. These results indicate that reorganization of higher levels of chromatin structure is an important regulated step in BRCA1-mediated nuclear functions.
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PMID:BRCA1-induced large-scale chromatin unfolding and allele-specific effects of cancer-predisposing mutations. 1173 4

We demonstrate here that the E2F1 induced by DNA damage can bind to and promote the apoptotic function of p53 via the cyclin A binding site of E2F1. This function of E2F1 does not require its DP-1 binding, DNA binding, or transcriptional activity and is independent of mdm2. All the cyclin A binding E2F family members can interact and cooperate with p53 to induce apoptosis. This suggests a novel role for E2F in regulating apoptosis in response to DNA damage. Cyclin A, but not cyclin E, prevents E2F1 from interacting and cooperating with p53 to induce apoptosis. However, in response to DNA damage, cyclin A levels decrease, with a concomitant increase in E2F1-p53 complex formation. These results suggest that the binding of E2F1 to p53 can specifically stimulate the apoptotic function of p53 in response to DNA damage.
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PMID:Novel function of the cyclin A binding site of E2F in regulating p53-induced apoptosis in response to DNA damage. 1173 24

Recent studies have shown the p19(ARF) tumor suppressor to be involved in the response to oncogenic stress by regulating the activity of p53. This response is mediated by antagonizing the function of Mdm2, a negative regulator of p53, indicating a pathway for tumor suppression that involves numerous genes altered in human tumors. We previously described a transgenic mouse brain tumor model in which oncogenic stress, provided by cell-specific inactivation of the pRb pathway, triggers a p53-dependent apoptotic response. This response suppresses the growth of developing tumors and thus represents a bona fide in vivo tumor suppressor activity. We further showed that E2F1, a transcription factor known to induce p19(ARF) expression, was required for the response. Here, we use a genetic approach to test whether p19(ARF) functions to transduce the signal from E2F1 to p53 in this tumor suppression pathway. Contrary to the currently accepted hypothesis, we show that a deficiency in p19(ARF) has no impact on p53-mediated apoptosis or tumor suppression in this system. All measures of p53 function, including the level of apoptosis induced by pRb inactivation, the expression of p21 (a p53-responsive gene), and the rate of tumor growth, were comparable in mice with and without a functional p19(ARF) gene. Thus, although p19(ARF) is required in some cell types to transmit an oncogenic response signal to p53, it is dispensable for this function in an in vivo epithelial system. These results underscore the complexity of p53 tumor suppression and further indicate the existence of distinct cell-specific pathways that respond to similar stimuli.
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PMID:p19(ARF) is dispensable for oncogenic stress-induced p53-mediated apoptosis and tumor suppression in vivo. 1173 48

Treatment with thyroid hormone (TH) results in shrinkage of a thyrotropic tumor grown in a hypothyroid host. We used microarray and Northern analysis to assess the changes in gene expression that preceded tumor involution. Of the 1,176 genes on the microarray, 7 were up-regulated, whereas 40 were decreased by TH. Many of these were neuroendocrine in nature and related to growth or apoptosis. When we examined transcripts for cell cycle regulators only cyclin-dependent kinase 2, cyclin A and p57 were down-regulated, whereas p15 was induced by TH. Retinoblastoma protein, c-myc, and mdm2 were unchanged, but E2F1 was down-regulated. TH also decreased expression of brain-derived neurotrophic factor, its receptor trkB, and the receptor for TRH. These, in addition to two other genes, neuronatin and PB cadherin, which were up- and down-regulated, respectively, showed a more rapid response to TH than the cell cycle regulators and may represent direct targets of TH. Finally, p19ARF was dramatically induced by TH, and although this protein can stabilize p53 by sequestering mdm2, we found no increase in p53 protein up to 48 h of treatment. In summary, we have described early changes in the expression of genes that may play a role in TH-induced growth arrest of a thyrotropic tumor. These include repression of specific growth factor and receptors and cell cycle genes as well as induction of other factors associated with growth arrest and apoptosis.
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PMID:Early gene expression changes preceding thyroid hormone-induced involution of a thyrotrope tumor. 1179 85

Primary fibroblasts respond to activated H-RAS(V12) by undergoing premature arrest, which resembles replicative senescence. This irreversible 'fail-safe mechanism' requires p19(ARF), p53 and the Retinoblastoma (Rb) family: upon their disruption, RAS(V12)-expressing cells fail to undergo senescence and continue to proliferate. Similarly, co-expression of oncogenes such as c-MYC or E1A rescues RAS(V12)-induced senescence. To identify novel genes that allow escape from RAS(V12)-induced senescence, we designed an unbiased, retroviral complementary DNA library screen. We report on the identification of DRIL1, the human orthologue of the mouse Bright and Drosophila dead ringer transcriptional regulators. DRIL1 renders primary murine fibroblasts unresponsive to RAS(V12)-induced anti-proliferative signalling by p19(ARF)/p53/p21(CIP1), as well as by p16(INK4a). In this way, DRIL1 not only rescues RAS(V12)-induced senescence but also causes these fibroblasts to become highly oncogenic. Furthermore, DRIL1 immortalizes mouse fibroblasts, in the presence of high levels of p16(INK4a). Immortalization by DRIL1, whose product binds the pRB-controlled transcription factor E2F1 (ref. 8), is correlated with induction of E2F1 activity. Correspondingly, DRIL1 induces the E2F1 target Cyclin E1, overexpression of which is sufficient to trigger escape from senescence. Thus, DRIL1 disrupts cellular protection against RAS(V12)-induced proliferation downstream of the p19(ARF)/p53 pathway.
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PMID:A functional screen identifies hDRIL1 as an oncogene that rescues RAS-induced senescence. 1181 99

The ARF tumor suppressor participates in a p53-dependent apoptotic pathway that is stimulated in response to some oncogenic stimuli. The E2F1 transcription factor is a critical downstream target of the Rb tumor suppressor and, when active, can promote proliferation as well as apoptosis. The finding that E2F1 transcriptionally regulates the ARF gene has led to the suggestion that ARF contributes to E2F1-induced apoptosis. Counter to this hypothesis, this study demonstrates not only that ARF is unnecessary for E2F1 to induce apoptosis but also that inactivation of ARF actually enhances the ability of E2F1 to promote apoptosis. Inactivation of ARF also cooperates with E2F1 activity to promote entry into the S phase of the cell cycle. This relationship between ARF and E2F1 is demonstrated in transgenic epidermis in vivo and in mouse embryo fibroblast cultures in vitro. In contrast, the ability of Myc to induce apoptosis is diminished in the absence of ARF. E2F1 induces the accumulation of p53 in the absence of ARF, and this is associated with the phosphorylation of p53 on several residues. These findings demonstrate that ARF is a negative regulator of E2F1 activity and is not required for E2F1-induced apoptosis.
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PMID:ARF differentially modulates apoptosis induced by E2F1 and Myc. 1183 3

E2F1 induces apoptosis via both p53-dependent and p53-independent mechanisms. The direct targets in the p53-independent pathway remain enigmatic; however, the induction of this pathway does not require the transactivation domain of E2F1. Using cells that are defective in p53 activation, we show that E2F1 potently represses the expression of Mcl-1--an anti-apoptotic Bcl-2 family member whose depletion results in apoptosis. We also show that this transcriptional repression is direct and dependent upon E2F1's DNA-binding domain, but does not require the transactivation domain of E2F1. Consistent with this DNA binding requirement of E2F1 to repress Mcl-1, we show that E2F1 binds to the Mcl-1 promoter both in vitro and in vivo, and have identified the DNA element (-143/-117) within this promoter that is required for E2F1 binding and repression. Additionally, cell lines constitutively expressing Mcl-1 are resistant to E2F1-mediated apoptosis--suggesting that Mcl-1 downregulation is a necessary event in the p53-independent apoptotic process. Thus, we identify a p53 family-independent mechanism of E2F1-induced apoptosis in which E2F1 directly represses Mcl-1 expression.
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PMID:Direct repression of the Mcl-1 promoter by E2F1. 1185 79

The p16/RB/E2F regulatory pathway, which controls transit through the G1 restriction point of the cell cycle, is one of the most frequent targets of genetic alterations in human cancer. Any of these alterations results in the deregulated expression of the transcription factor E2F, one of the key mediators of cell cycle progression. Under these conditions, E2F1 also participates in the induction of apoptosis by a p53-dependent pathway, and independently of p53. Recently, we identified the p53-homolog p73 as a first direct target of p53-independent apoptosis. Here, we used a cDNA microarray to screen an inducible E2F1-expressing Saos-2 cell line for E2F1 target genes. Expression analysis by cDNA microarray and RT-PCR revealed novel E2F1 target genes involved in E2F1-regulated cellular functions such as cell cycle control, DNA replication and apoptosis. In addition, the identification of novel E2F1 target genes participating in the processes of angiogenesis, invasion and metastasis supports the view that E2F1 plays a central role in many aspects of cancer development. These results provide new insight into the role of E2F1 in tumorigenesis as a basis for the development of novel anti-cancer therapeutics.
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PMID:Gene expression changes in response to E2F1 activation. 1193 41

The Mdm2 proto-oncogene is amplified and over-expressed in a variety of tumors. One of the major functions of Mdm2 described to date is its ability to modulate the levels and activity of the tumor suppressor protein p53. Mdm2 binds to the N-terminus of p53 and, through its action as an E3 ubiquitin ligase, targets p53 for rapid proteasomal degradation. Mdm2 can also bind to other cellular proteins such as hNumb, E2F1, Rb and Akt; however, the biological significance of these interactions is less clear. To gain insight into the function of Mdm2 in vivo, we have generated a transgenic Drosophila strain bearing the mouse Mdm2 gene. Ectopic expression of Mdm2, using the UAS/GAL4 system, causes eye and wing phenotypes in the fly. Analysis of wing imaginal discs from third instar larvae showed that expression of Mdm2 induces apoptosis. Crosses did not reveal genetic interactions between Mdm2 and the Drosophila homolog of E2F, Numb and Akt. These transgenic flies may provide a unique experimental model for exploring the molecular interactions of Mdm2 in a developmental context.
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PMID:Overexpression of mouse Mdm2 induces developmental phenotypes in Drosophila. 1194 25


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