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)

Aberrant NF-kappaB activity promotes tumorigenesis. However, NF-kappaB also inhibits tumor growth where tumor suppressor pathways remain unaltered. Thus, its role in tumorigenesis depends upon the function of other cellular factors. Tumor suppressor SMAR1 down-modulated in high grade breast cancers is regulated by p53 and is reported to interact and stabilize p53. Because both SMAR1 and NF-kappaB are involved in tumorigenesis, we investigated the effect of SMAR1 upon NF-kappaB activity. We show that SMAR1 induction by doxorubicin or overexpression produces functional NF-kappaB complexes that are competent for binding to NF-kappaB consensus sequence. However, SMAR1 induced p65-p50 complex is phosphorylation- and transactivation-deficient. Induction of functional NF-kappaB complexes stems from down-regulation of IkappaBalpha transcription through direct binding of SMAR1 to the matrix attachment region site present in IkappaBalpha promoter and recruitment of corepressor complex. Real time PCR array for NF-kappaB target genes revealed that SMAR1 down-regulates a subset of NF-kappaB target genes that are involved in tumorigenesis. We also show that SMAR1 inhibits tumor necrosis factor alpha-induced induction of NF-kappaB suggesting that activation of NF-kappaB by SMAR1 is independent and different from classical pathway. Thus, for the first time we report that a tumor suppressor protein SMAR1 can modulate NF-kappaB transactivation and inhibit tumorigenesis by regulating NF-kappaB target genes.
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PMID:Tumor suppressor SMAR1 represses IkappaBalpha expression and inhibits p65 transactivation through matrix attachment regions. 1898 Nov 84

Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell (or cells) of origin has not been rigorously determined. We previously reported mouse models based on conditional inactivation of the human astrocytoma-relevant tumor suppressors p53, Nf1, and Pten, wherein through somatic loss of heterozygosity, mutant mice develop tumors with 100% penetrance. In the present study, we show that tumor suppressor inactivation in neural stem/progenitor cells is both necessary and sufficient to induce astrocytoma formation. We demonstrate in vivo that transformed cells and their progeny undergo infiltration and multilineage differentiation during tumorigenesis. Tumor suppressor heterozygous neural stem/progenitor cultures from presymptomatic mice show aberrant growth advantage and altered differentiation, thus identifying a pretumorigenic cell population.
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PMID:Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. 1911 80

Tumor suppressor gene PTEN is important in the initiation and progression of human prostate carcinoma, whereas the role of TP53 remains controversial. Since Pten/Trp53 double conditional knockout mice show earlier onset and fast progression of prostate cancer when compared to Pten knockout mice, we asked whether heterozygosity of these two tumor suppressor genes was sufficient to accelerate prostatic tumorigenesis. To answer this question we examined prostatic lesion progression of Pten/Trp53 double heterozygous mice and a series of controls such as Pten heterozygous, Pten conditional knockout, Trp53 heterozygous and Trp53 knockout mice. Tissue recombination of adult prostatic epithelium coupled with embryonic rat seminal vesicle mesenchyme was used as a tool to stimulate prostatic epithelial proliferation. In our study, high-grade prostatic intraepithelial neoplasia (PIN) was found with high frequency at 8 weeks post-tissue recombination transplantation. PIN lesions in Pten/Trp53 double heterozygous mice were more severe than those seen in Pten heterozygous alone. Furthermore, morphologic features attributable to Pten or Trp53 loss appeared to be enhanced in double heterozygous tissues. LOH analysis of Pten and Trp53 in genomic DNA collected from high-grade PIN lesions in Pten heterozygous and Pten/Trp53 double heterozygous mice showed an intact wild-type allele for both genes in all samples examined. In conclusion, simultaneous heterozygosity of Pten and Trp53 accelerates prostatic tumorigenesis in this mouse model of prostate cancer independently of loss of heterozygosity of either gene.
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PMID:Simultaneous haploinsufficiency of Pten and Trp53 tumor suppressor genes accelerates tumorigenesis in a mouse model of prostate cancer. 1928 69

Tumor suppressor genes, such as p53, RB, the INK4-ARF family and PML, suppress malignant transformation by regulating cell cycle progression, ensuring the fidelity of DNA replication and chromosomal segregation, or by inducing apoptosis in response to potentially deleterious events. In myeloid leukemia, hematopoietic differentiation resulting from highly coordinated, stage-wise expression of myeloid transcription and soluble signaling factors is disrupted leading to a block in terminal differentiation and uncontrolled proliferation. This virtually always involves functional inactivation or genetic disruption of one or several tumor suppressor genes in order to circumvent their checkpoint control and apoptosis-inducing functions. Hence, reactivation of tumor suppressor gene function has therapeutic potential and can possibly enhance conventional cytotoxic chemotherapy. In this review, we focus on the role of different tumor suppressor genes in myeloid differentiation and leukemogenesis, and discuss implications for therapy.
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PMID:Tumor suppressor genes in myeloid differentiation and leukemogenesis. 1928 82

The cellular composition of atherosclerotic lesions is determined by many factors including cell infiltration, proliferation and cell death. Tumor suppressor gene p53 has been shown to regulate both cell proliferation and cell death in many cell types. In the present study, we investigated the role of macrophage p53 in the pathogenesis of early and advanced atherosclerosis. Using the Cre-loxP system we found that absence of macrophage p53 (p53(del)) strongly reduces apoptosis of macrophages both in early and advanced atherosclerotic lesions (-59% and -37%, respectively). Consequently, in advanced atherosclerosis, reduced apoptosis upon absence of macrophage p53, coincided with increased acellular necrotic core formation (+96%), increased macrophage content (+24%), and reduced cholesterol cleft accumulation (-41%). Proliferation was not affected by the absence of macrophage p53 in both early and advanced atherosclerosis. However, these significant changes in lesional cell death did not affect total lesion area in both early and advanced atherosclerosis, neither in the aortic root nor in the aortic arch and thoracic aorta in ApoE-deficient mice. Our data demonstrate that macrophage p53 is an important regulator of macrophage apoptosis, thereby preventing necrotic death of lesional macrophages. The regulation of this cell death balance directly affects lesion composition.
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PMID:Macrophage p53 controls macrophage death in atherosclerotic lesions of apolipoprotein E deficient mice. 1960 84

Tumor suppressor SMAR1 is known to be involved in regulation of cell cycle and apoptotic genes transcription. It also directly interacts and stabilizes p53 through phosphorylation at serine-15 residue. Although the functions of SMAR1 are mainly restricted to the nucleus, we report its novel function with the cytoplasm. We show that SMAR1 directly interacts and inhibits AKR1a4 enzyme activity. Interestingly, AKR1a4 enzyme activity is elevated in higher grades of breast cancer where SMAR1 expression is drastically downregulated. Higher AKR1a4 activity protects the cancer cells from anticancer drugs and free radical stress. Through increased metabolism, ARK1a4 helps fulfilling higher energy needs required by cancer cell. The present study delineates yet another facet of tumor suppressor activity of SMAR1 in the cytoplasm. We also depict that upon stress, ATM kinase leads to dissociation of SMAR1-AKR1a4 complex through nuclear translocation of SMAR1 causing elevated AKR1a4 activity. Nuclear SMAR1 causes cell cycle arrest giving ample time for DNA damage repair, while AKR1a4 scavenges the excess free radicals which may further cause DNA damage. Thus, we propose a novel mechanism of regulation of oxidative stress by ATM through modulation of SMAR1-AKR1a4 complex. Further, we show that a small peptide derived from SMAR1 induces free radical stress by inhibiting AKR1a4 enzyme activity, which can be a potential anticancer therapeutic agent.
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PMID:SMAR1 regulates free radical stress through modulation of AKR1a4 enzyme activity. 2009 5

We observed an unusually large subependymoma in a female patient with congenital aniridia. To analyze the genetic mechanisms of tumorigenesis, we first examined the paired box 6 (PAX6) gene using both tumor tissue and peripheral lymphocytes. Tumor suppressor activity has been proposed for PAX6 in gliomas, in addition to its well-known role in the eye development. Using genomic quantitative PCR and loss of heterozygosity analysis, we identified hemizygous deletions in the 5'-region of PAX6. In lymphocytes, the deletion within PAX6 spanned from between exons 6 and 7 to the 5'-upstream region of the gene, but did not reach the upstream gene, RNC1, which is reported to be associated with tumors. The subependymoma had an additional de novo deletion spanning from the intron 4 to intron 6 of PAX6, although we could not completely determine whether these two deletions are on the same chromosome or not. We also examined other potentially relevant tumor suppressor genes: PTEN, TP53 and SOX2. However, we detected no exonic mutations or deletions in these genes. Collectively, we speculate that the defect in PAX6 may have contributed to the extremely large size of the subependymoma, due to a loss of tumor suppressor activity in glial cell lineage.
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PMID:Giant subependymoma developed in a patient with aniridia: analyses of PAX6 and tumor-relevant genes. 2050 May 13

Landmark cancer genome resequencing efforts are leading to the identification of mutated genes in many types of cancer. The extreme diversity of mutations being detected presents significant challenges to subdivide causal from coincidental mutations to elucidate how disrupted regulatory networks drive cancer processes. Given that a common early perturbation in solid tumor initiation is bypass of matrix-dependent proliferation restraints, we sought to functionally interrogate colorectal cancer candidate genes (CAN-genes) to identify driver tumor suppressors. We have employed an isogenic human colonic epithelial cell (HCEC) model to identify suppressors of anchorage-independent growth by conducting a soft agar-based short hairpin RNA (shRNA) screen within the cohort of CAN-genes. Remarkably, depletion of 65 of the 151 CAN-genes tested collaborated with ectopic expression of K-RAS(V12) and/or TP53 knockdown to promote anchorage-independent proliferation of HCECs. In contrast, only 5 of 362 random shRNAs (1.4%) enhanced soft agar growth. We have identified additional members of an extensive gene network specifying matrix-dependent proliferation, by constructing an interaction map of these confirmed progression suppressors with approximately 700 mutated genes that were excluded from CAN-genes, and experimentally verifying soft agar growth enhancement in response to depletion of a subset of these genes. Collectively, this study revealed a profound diversity of nodes within a fundamental tumor suppressor network that are susceptible to perturbation leading to enhanced cell-autonomous anchorage-independent proliferative fitness. Tumor suppressor network fragility as a paradigm within this and other regulatory systems perturbed in cancer could, in large part, account for the heterogeneity of somatic mutations detected in tumors.
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PMID:Functional parsing of driver mutations in the colorectal cancer genome reveals numerous suppressors of anchorage-independent growth. 2152 59

Cancer is caused by multiple genetic alterations leading to uncontrolled cell proliferation through multiple pathways. Malignant cells arise from a variety of genetic factors, such as mutations in tumor suppressor genes (TSGs) that are involved in regulating the cell cycle, apoptosis, or cell differentiation, or maintenance of genomic integrity. Tumor suppressor mouse models are the most frequently used animal models in cancer research. The anti-tumorigenic functions of TSGs, and their role in development and differentiation, and inhibition of oncogenes are discussed. In this review, we summarize some of the important transgenic and knockout mouse models for TSGs, including Rb, p53, Ink4a/Arf, Brca1/2, and their related genes.
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PMID:Transgenic and knockout mice models to reveal the functions of tumor suppressor genes. 2183 19

Tumor suppressor genes regulate diverse cellular activities including DNA damage repair, cell cycle arrest, mitogenic signaling, cell differentiation, migration, and programmed cell death. In this review the tumor suppressor genes p53, FoxO, retinoblastoma (RB), p21, p16, and breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) and their roles in oxidative stress are summarized with a focus on the links and interplay between their pathways and reactive oxygen species (ROS). The results of a number of studies have demonstrated an antioxidant role for tumor suppressor proteins, activating the expression of some well-known antioxidant genes in response to oxidative stress. On the other hand, recent studies have revealed a pro-oxidant role for p53 by which cellular ROS are increased by enhanced transcription of proapoptotic genes. A tightly regulated feedback loop between ROS and FoxO proteins, with ROS regulating FoxO activity through posttranslational modifications and protein interactions and FoxO controlling intracellular ROS levels, has been demonstrated. Furthermore, these studies have shown that FoxO transcription factors and p38 mitogen-activated protein kinases may interact with the RB pathway under stress conditions. In addition, cellular senescence studies established an unexpected role for ROS in inducing and maintaining senescence-induced tumor suppression that blocks cytokinesis to ensure senescent cells never divide again. p21 and p16 have been shown to act as tumor suppressor proteins and this function extends beyond cell cycle control and includes important roles in regulating oxidative stress. Consequently, these important interactions indicate a critical potential role for tumor suppressor genes in the cellular response against oxidative stress and emphasize links between ROS and tumor suppressor genes that might be therapeutic targets in oxidative damage-associated diseases.
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PMID:Tumor suppressor genes and ROS: complex networks of interactions. 2201 31


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