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)

In response to ionizing radiation, p53 plays a critical role in regulating DNA repair and apoptosis. Among multiple phosphorylation sites, evidence suggests that Ser46 promotes apoptotic cell death through mitochondrial outer membrane permeabilization (MOMP) and subsequent activation of the caspase 7-PARP pathway. Therefore, we investigated which phosphatase regulates Ser46 after ionizing radiation, reasoning that the responsible phosphatase should be a target for radiosensitization. We determined that both inhibition of PP2A by the cell-permeable inhibitor calyculin A and knockdown of PP2A by RNAi (a) enhanced Ser46 phosphorylation in p53 and (b) induced coincident caspase 7 and PARP cleavage in response to ionizing radiation. Furthermore, mutation of p53 Ser46 to Ala attenuated ionizing radiation-induced apoptotic signaling. Consequently, we concluded that PP2A regulates ionizing radiation-induced apoptotic signaling through dephosphorylation of p53 Ser46.
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PMID:PP2A regulates ionizing radiation-induced apoptosis through Ser46 phosphorylation of p53. 1913 22

SV40 transforms cells through the action of two oncoproteins, large T antigen and small t antigen. Small t antigen targets phosphatase PP2A, while large T antigen stimulates cell proliferation and survival by action on multiple proteins, including the tumor suppressors Rb and p53. Large T antigen also binds components of the transcription initiation complex and several transcription factors. We examined global gene expression in SV40-transformed mouse embryo fibroblasts, and in enterocytes obtained from transgenic mice. SV40 transformation alters the expression of approximately 800 cellular genes in both systems. Much of this regulation is observed in both MEFs and enterocytes and is consistent with T antigen action on the Rb-E2F pathway. However, the regulation of many genes is cell-type specific, suggesting that unique signaling pathways are activated in different cell types upon transformation, and that the consequences of SV40 transformation depends on the type of cell targeted.
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PMID:Cell-type specific regulation of gene expression by simian virus 40 T antigens. 1920 38

Reactive oxygen species (ROS) regulate the strength and duration of signaling through redox-dependent signal transduction pathways via the cyclic oxidation/reduction of cysteine residues in kinases, phosphatases, and other regulatory factors. Signaling circuits may be segregated in organelles or other subcellular domains with distinct redox states, permitting them to respond independently to changes in the oxidation state of two major thiol reductants, glutathione and thioredoxin. Studies in yeast, and in complex eukaryotes, show that oscillations in oxygen consumption, energy metabolism, and redox state are intimately integrated with cell cycle progression. Because signaling pathways play specific roles in different phases of the cell cycle and the hierarchy of redox-dependent regulatory checkpoints changes during cell cycle progression, the effects of ROS on cell fate vary during the cell cycle. In G1, ROS stimulate mitogenic pathways that control the activity of cyclin-dependent kinases (CDKs) and phosphorylation of the retinoblastoma protein (pRB), thereby regulating S-phase entry. In response to oxidative stress, Nrf2 and Foxo3a promote cell survival by inducing the expression of antioxidant enzymes and factors involved in cell cycle withdrawal, such as the cyclin-dependent kinase inhibitor (CKI) p27. In S phase, ROS induce S-phase arrest via PP2A-dependent dephosphorylation of pRB. In precancerous cells, unconstrained mitogenic signaling by activated oncogenes induces replication stress in S phase, which activates the DNA-damage response and induces cell senescence. A number of studies suggest that interactions of ROS with the G1 CDK/CKI network play a fundamental role in senescence, which is considered a barrier to tumorigenesis. Adaptive responses and loss of checkpoint proteins such as p53 and p16(INK4a) allow tumor cells to tolerate constitutive mitogenic signaling and enhanced production of ROS, leading to altered redox status in many fully transformed cells. Alterations in oxidant and energy metabolism of cancer cells have emerged as fertile ground for new therapeutic targets. The present challenge is to identify redox-dependent targets relevant to each cell cycle phase, to understand how these targets control fate decisions, and to describe the mechanisms that link metabolism to cell cycle progression.
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PMID:The cell cycle is a redox cycle: linking phase-specific targets to cell fate. 1948 41

Simian Virus 40 (SV40) and Mouse Polyoma Virus (PY) are small DNA tumor viruses that have been used extensively to study cellular transformation. The SV40 early region encodes three tumor antigens, large T (LT), small T (ST) and 17KT that contribute to cellular transformation. While PY also encodes LT and ST, the unique middle T (MT) generates most of the transforming activity. SV40 LT mediated transformation requires binding to the tumor suppressor proteins Rb and p53 in the nucleus and ST binding to the protein phosphatase PP2A in the cytoplasm. SV40 LT also binds to several additional cellular proteins including p300, CBP, Cul7, IRS1, Bub1, Nbs1 and Fbxw7 that contribute to viral transformation. PY MT transformation is dependent on binding to PP2A and the Src family protein tyrosine kinases (PTK) and assembly of a signaling complex on cell membranes that leads to transformation in a manner similar to Her2/neu. Phosphorylation of MT tyrosine residues activates key signaling molecules including Shc/Grb2, PI3K and PLCgamma1. The unique contributions of SV40 LT and ST and PY MT to cellular transformation have provided significant insights into our understanding of tumor suppressors, oncogenes and the process of oncogenesis.
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PMID:Cellular transformation by Simian Virus 40 and Murine Polyoma Virus T antigens. 1950 49

We investigated the role of histone deacetylase 4 (HDAC4) using RNA interference (RNAi) and knockout cells to specifically address its role in cell cycle progression in tumor and normal cells. Ablation of HDAC4 led to growth inhibition in human tumor cells but not to detectable effects in normal human dermal fibroblasts (NHDF) or myelopoietic progenitors. HDAC4-/+ or HDAC4-/- murine embryonic fibroblasts showed no detectable growth defects. On the other hand, HDAC4 RNAi in HeLa cells produced mitotic arrest followed by caspase-dependent apoptosis. Mitotically arrested cells showed chromosome segregation defects. Even though the growth of both p53-wild-type and p53-null tumor cells were affected by HDAC4 ablation, segregation defects were observed only in p53-null cells. HDAC4 associates with the PP2A-B56 regulatory subunit, which is known to be involved in chromosome segregation, and RNAi of either the structural subunit A or the regulatory subunit B56 of PP2A also caused chromosome segregation defects. We conclude that HDAC4 is required for cell cycle progression of tumor cells by multiple mechanisms, one of which seems to be specific to p53-deficient cells through chromosome segregation defects. On the contrary, HDAC4 is not required for the progression of NHDF. We therefore suggest that systemic selective interference with the expression or function of HDAC4 is expected to have a significant therapeutic window, in particular, for p53-deficient tumors.
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PMID:Loss of histone deacetylase 4 causes segregation defects during mitosis of p53-deficient human tumor cells. 1962 75

We have previously reported that ADP ribosylation factor like 2 (Arl2), a small GTPase, content influences microtubule dynamics and cell cycle distribution in breast tumor cells, as well as the degree and distribution of phosphorylated P53. Here we show, in two different human breast adenocarcinoma models, that Arl2 content has a major impact on breast tumor cell aggressivity both in vitro and in vivo. Cells with reduced content of Arl2 displayed reduced contact inhibition, increased clonogenic or cluster formation as well as a proliferative advantage over control cells in an in vitro competition assay. These cells also caused larger tumors in SCID mice, a phenotype which was mimicked by the in vivo administration of siRNA directed against Arl2. Cells with increased Arl2 content displayed reduced aggressivity, both in vitro and in vivo, with enhanced necrosis and were also found to contain increased PP2A phosphatase activity. A rt-PCR analysis of fresh human tumor breast samples suggested that low Arl2 expression was associated with larger tumor size and greater risk of lymph node involvement at diagnosis. These data underline the role of Arl2, a small GTPase, as an important regulator of breast tumor cell aggressivity, both in vitro and in vivo.
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PMID:ADP ribosylation factor like 2 (Arl2) regulates breast tumor aggressivity in immunodeficient mice. 1982 7

In response to DNA double strand breaks, the histone variant H2AX at the break site is phosphorylated at serine 139 by DNA damage sensor kinases such as ataxia telangiectasia-mutated, forming gamma-H2AX. This phosphorylation event is critical for sustained recruitment of other proteins to repair the break. After repair, restoration of the cell to a prestress state is associated with gamma-H2AX dephosphorylation and dissolution of gamma-H2AX-associated damage foci. The phosphatases PP2A and PP4 have previously been shown to dephosphorylate gamma-H2AX. Here, we demonstrate that the wild-type p53-induced phosphatase 1 (WIP1) also dephosphorylates gamma-H2AX at serine 139 in vitro and in vivo. Overexpression of WIP1 reduces formation of gamma-H2AX foci in response to ionizing and ultraviolet radiation and blocks recruitment of MDC1 (mediator of DNA damage checkpoint 1) and 53BP1 (p53 binding protein 1) to DNA damage foci. Finally, these inhibitory effects of WIP1 on gamma-H2AX are accompanied by WIP1 suppression of DNA double strand break repair. Thus, WIP1 has a homeostatic role in reversing the effects of ataxia telangiectasia-mutated phosphorylation of H2AX.
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PMID:Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. 2011 29

A chronic neuron loss is the cardinal pathology in Alzheimer disease (AD), but it is still not understood why most neurons in AD brain do not accomplish apoptosis even though they are actually exposed to an environment with enriched proapoptotic factors. Protein phosphatase-2A inhibitor-2 (I(2)(PP2A)), an endogenous PP2A inhibitor, is significantly increased in AD brain, but the role of I(2)(PP2A) in AD-like neuron loss is elusive. Here, we show that I(2)(PP2A) regulates p53 and Akt correlatively. The mechanisms involve activated transcription and p38 MAPK activities. More importantly, we demonstrate that the simultaneous activation of Akt induced by I(2)(PP2A) counteracts the hyperactivated p53-induced cell apoptosis. Furthermore, I(2)(PP2A), p53 and Akt are all elevated in the brain of mouse model and AD patients. Our results suggest that the increased I(2)(PP2A) may trigger apoptosis by p53 upregulation, but due to simultaneous activation of Akt, the neurons are aborted from the apoptotic pathway. This finding contributes to the understanding of why most neurons in AD brain do not undergo apoptosis.
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PMID:I(2)(PP2A) regulates p53 and Akt correlatively and leads the neurons to abort apoptosis. 2013 2

Microcystin produced by cyanobacteria in diverse water systems is a potent hepatotoxin that has been documented to induce hepatocyte apoptosis and liver injury. There are more than eighty reported microcystins. The present work aimed at investigating the apoptotic effect of MC-RR (a common member of microcystin family), and its related mechanism. MC-RR was administered orally to ICR mice for 7 days with different dosages. Apoptotic cell death in liver was detected by TUNEL assay, and the expression levels of Bcl-2, Bax and p53, GRP 78 and CHOP which have been reported to be related to apoptosis and ER stress were determined via western-blot. The activity of PP2A was measured using the serine-threonine phosphatase assay system and PP2A A subunit expression at both transcription and protein levels was measured by RT-PCR and western blot, respectively. A significant difference was observed on the number of TUNEL positive liver cells between the control and MC-RR-treated groups. The expression levels of Bcl-2, Bax, p53, and GRP 78 in MC-RR-treated groups were altered significantly compared to the control, but no obvious alteration was found in CHOP expression. The PP2A activity and A subunit expression did not manifest any obvious change at both transcription and protein levels. The results indicated that oral exposure to MC-RR can cause apoptosis as well as moderate ER stress in mice liver. The mitochondrial pathway via Bcl-2 family members may contribute to the apoptosis. However, PP2A may not be involved in the regulation of apoptotic process under the current conditions.
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PMID:The apoptotic effect of oral administration of microcystin-RR on mice liver. 2019 64

Earlier studies have shown both p53-dependent and -independent tumor-suppressive functions of B56gamma-specific protein phosphatase 2A (B56gamma-PP2A). In the absence of p53, B56gamma-PP2A can inhibit cell proliferation and cell transformation by an unknown mechanism. In the presence of p53, on DNA damage, a complex including B56gamma-PP2A and p53 is formed, which leads to Thr55 dephosphorylation of p53, induction of the p53 transcriptional target p21 and inhibition of cell proliferation. In spite of its significance in inhibition of cell proliferation, no B56gamma mutations have been linked to human cancer to date. In this study, we first differentiate between the p53-dependent and -independent functions of B56gamma-PP2A by identifying a domain of the B56gamma protein required for interaction with p53. Within this region, we identify a B56gamma mutation, F395C, in lung cancer that disrupts the B56gamma-p53 interaction. More importantly, we show that F395C is unable to promote p53 Thr55 dephosphorylation, transcriptional activation of p21 and the p53-dependent tumor-suppressive function of PP2A. This finding provides a mechanistic basis for the p53-dependent and -independent functions of B56gamma-PP2A and establishes a critical link between B56gamma-PP2A p53-dependent tumor-suppressive function and tumorigenesis.
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PMID:A B56gamma mutation in lung cancer disrupts the p53-dependent tumor-suppressor function of protein phosphatase 2A. 2047 27


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