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)

Tumor suppressor p53-dependent stress response pathways play an important role in cell fate determination. In this study, we have found that glucose depletion promotes the phosphorylation of AMP-activated protein kinase catalytic subunit alpha (AMPKalpha) in association with a significant up-regulation of p53, thereby inducing p53-dependent apoptosis in vivo and in vitro. Thymocytes prepared from glucose-depleted wild-type mice but not from p53-deficient mice underwent apoptosis, which was accompanied by a remarkable phosphorylation of AMPKalpha and a significant induction of p53 as well as pro-apoptotic Bax. Similar results were also obtained in human osteosarcoma-derived U2OS cells bearing wild-type p53 following glucose starvation. Of note, glucose deprivation led to a significant accumulation of p53 phosphorylated at Ser-46, but not at Ser-15 and Ser-20, and a transcriptional induction of p53 as well as proapoptotic p53 AIP1. Small interference RNA-mediated knockdown of p53 caused an inhibition of apoptosis following glucose depletion. Additionally, apoptosis triggered by glucose deprivation was markedly impaired by small interference RNA-mediated depletion of AMPKalpha. Under our experimental conditions, down-regulation of AMPKalpha caused an attenuation of p53 accumulation and its phosphorylation at Ser-46. In support of these observations, enforced expression of AMPKalpha led to apoptosis and resulted in an induction of p53 at protein and mRNA levels. Furthermore, p53 promoter region responded to AMPKalpha and glucose deprivation as judged by luciferase reporter assay. Taken together, our present findings suggest that AMPK-dependent transcriptional induction and phosphorylation of p53 at Ser-46 play a crucial role in the induction of apoptosis under carbon source depletion.
 ...
PMID:Activation of AMP-activated protein kinase induces p53-dependent apoptotic cell death in response to energetic stress. 1805 5

Cisplatin is one of the most effective and widely used chemotherapeutic agents. However, one of the most salient limitations to the clinical application of cisplatin is the acquired or intrinsic drug resistance exhibited by some tumors. In the present study, we have assessed the potential of an intracellular energy balancing system as a target for augmentation of cisplatin sensitivity in tumors. AMP-activated protein kinase (AMPK) regulates the energy balance system by monitoring intracellular energy status. Here we demonstrate that AMPK is rapidly activated by cisplatin in AGS and HCT116 cancer cells. The inhibition of AMPK in those cells and in xenografts of HCT116 resulted in a remarkable increase in cisplatin-induced apoptosis, which was associated with hyper-induction of the tumor suppressor p53. We further showed that ERK, but not ATM (ataxia telangiectasia mutated) and ATR (ATM- and Rad3-related) kinases, was involved in the hyper-induction of p53 by the inhibition of cisplatin-induced AMPK. By way of contrast, cisplatin did not induce AMPK activation in HeLa cells, which appear to have a relatively high sensitivity to cisplatin-induced cytotoxicity, but expression of the constitutive active form of AMPK in HeLa cells resulted in a significant increase of cell viability after cisplatin treatment. Collectively, our data suggest that AMPK performs a pivotal function for protection against the cytotoxic effect of cisplatin, thereby implying that AMPK is one of the cellular factors determining the cellular sensitivity to cisplatin. On the basis of these observations, we propose that a strategy combining cisplatin and AMPK inhibition could be developed into a novel chemotherapeutic modality.
 ...
PMID:Inhibition of AMP-activated protein kinase sensitizes cancer cells to cisplatin-induced apoptosis via hyper-induction of p53. 3044 5

Lkb1 is a central regulator of cell polarity and energy metabolism through its capacity to activate the AMP-activated protein kinase (AMPK)-related family of protein kinases. Germ line-inactivating mutation of Lkb1 leads to Peutz-Jeghers syndrome, which is characterized by benign hamartomas and a susceptibility to malignant epithelial tumors. Mutations in Lkb1 are also found in sporadic carcinomas, most frequently in lung cancers associated with tobacco carcinogen exposure. The basis for Lkb1-dependent tumor suppression is not defined. Here, we uncover a marked sensitivity of Lkb1 mutant mice to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Lkb1(+/-) mice are highly prone to DMBA-induced squamous cell carcinoma (SCC) of the skin and lung. Confirming a cell autonomous tumor suppressor role of Lkb1, mice with epidermal-specific Lkb1 deletion are also susceptible to DMBA-induced SCC and develop spontaneous SCC with long latency. Restoration of wild-type Lkb1 causes senescence in tumor-derived cell lines, a process that can be partially bypassed by inactivation of the Rb pathway, but not by inactivation of p53 or AMPK. Our data indicate that Lkb1 is a potent suppressor of carcinogen-induced skin and lung cancers and that downstream targets beyond the AMPK-mTOR pathway are likely mediators of Lkb1-dependent tumor suppression.
 ...
PMID:LKB1 deficiency sensitizes mice to carcinogen-induced tumorigenesis. 1817 96

Platelet-derived growth factor (PDGF) is released from vascular smooth muscle cells (VSMCs), endothelial cells, or macrophages after percutaneous coronary intervention and is related with neointimal proliferation and restenosis. Berberine is a well-known component of the Chinese herb medicine Huanglian (Coptis chinensis), and is capable of inhibiting growth and endogenous PDGF synthesis in VSMCs after in vitro mechanical injury. We analyzed the effects of berberine on VSMC growth, migration, and signaling events after exogenous PDGF stimulation in vitro in order to mimic a post-angioplasty PDGF shedding condition. Pretreatment of VSMCs with berberine inhibited PDGF-induced proliferation. Berberine significantly suppressed PDGF-stimulated Cyclin D1/D3 and Cyclin-dependent kinase (Cdk) gene expression. Moreover, berberine increased the activity of AMP-activated protein kinase (AMPK), which led to phosphorylation activation of p53 and increased protein levels of the Cdk inhibitor p21(Cip1). Compound C, an AMPK inhibitor, partly but significantly attenuated berberine-elicited growth inhibition. In addition, stimulation of VSMCs with PDGF led to a transient increase in GTP-bound, active form of Ras, Cdc42 and Rac1, as well as VSMC migration. However, pretreatment with berberine significantly inhibited PDGF-induced Ras, Cdc42 and Rac1 activation and cell migration. Co-treatment with farnesyl pyrophosphate and geranylgeranyl pyrophosphate drastically reversed berberine-mediated anti-proliferative and migratory effects in VSMCs. Based on these findings, we conclude that berberine inhibited PDGF-induced VSMC growth via activation of AMPK/p53/p21(Cip1) signaling while inactivating Ras/Rac1/Cyclin D/Cdks and suppressing PDGF-stimulated migration via inhibition of Rac1 and Cdc42. These observations offer a molecular explanation for the anti-proliferative and anti-migratory properties of berberine.
 ...
PMID:Berberine inhibits platelet-derived growth factor-induced growth and migration partly through an AMPK-dependent pathway in vascular smooth muscle cells. 1859 Jul 25

SIRT1 is a member of a highly conserved gene family (sirtuins) encoding nicotinamide adenine dinucleotide (NAD)(+)-dependent deacetylases, originally found to deacetylate histones leading to increased DNA stability and prolonged survival in yeast and higher organisms, including mammals. SIRT1 has been found to function as a deacetylase for numerous protein targets involved in various cellular pathways, including stress responses, apoptosis and axonal degeneration. However, the role of SIRT1 in ultraviolet (UV) signalling pathways remains unknown. Using cell culture and Western blot analysis in this study we found that SIRT1 is expressed in cultured human skin keratinocytes. Both UV radiation and H(2)O(2), two major inducers of skin cell damage, down-regulate SIRT1 in a time- and dose-dependent manner. We observed that reactive oxygen species-mediated JNK activation is involved in this SIRT1 down-regulation. SIRT1 activator, resveratrol, which has been considered as an important antioxidant, protects against UV- and H(2)O(2)-induced cell death, whereas SIRT inhibitors such as sirtinol and nicotinamide enhance cell death. Activation of SIRT1 negatively regulates UV- and H(2)O(2)-induced p53 acetylation, because nicotinamide and sirtinol as well as SIRT1 siRNA enhance UV- and H(2)O(2)-induced p53 acetylation, whereas SIRT1 activator resveratrol inhibits it. We also found that SIRT1 is involved in UV-induced AMP-activated protein kinase (AMPK) and downstream acetyl-CoA carboxylase (ACC), phosphofructose kinase-2 (PFK-2) phosphorylation. Collectively, our data provide new insights into understanding of the molecular mechanisms of UV-induced skin aging, suggesting that SIRT1 activators such as resveratrol could serve as new anti-skin aging agents.
 ...
PMID:SIRT1 confers protection against UVB- and H2O2-induced cell death via modulation of p53 and JNK in cultured skin keratinocytes. 1868 8

AMP-activated protein kinase or AMPK is an evolutionarily conserved sensor of cellular energy status, activated by a variety of cellular stresses that deplete ATP. However, the possible involvement of AMPK in UV- and H(2)O(2)-induced oxidative stresses that lead to skin aging or skin cancer has not been fully studied. We demonstrated for the first time that UV and H(2)O(2) induce AMPK activation (Thr(172) phosphorylation) in cultured human skin keratinocytes. UV and H(2)O(2) also phosphorylate LKB1, an upstream signal of AMPK, in an epidermal growth factor receptor-dependent manner. Using compound C, a specific inhibitor of AMPK and AMPK-specific small interfering RNA knockdown as well as AMPK activator, we found that AMPK serves as a positive regulator for p38 and p53 (Ser(15)) phosphorylation induced by UV radiation and H(2)O(2) treatment. We also observed that AMPK serves as a negative feedback signal against UV-induced mTOR (mammalian target of rapamycin) activation in a TSC2-dependent manner. Inhibiting mTOR and positively regulating p53 and p38 might contribute to the pro-apoptotic effect of AMPK on UV- or H(2)O(2)-treated cells. Furthermore, activation of AMPK also phosphorylates acetyl-CoA carboxylase or ACC, the pivotal enzyme of fatty acid synthesis, and PFK2, the key protein of glycolysis in UV-radiated cells. Collectively, we conclude that AMPK contributes to UV- and H(2)O(2)-induced apoptosis via multiple mechanisms in human skin keratinocytes and AMPK plays important roles in UV-induced signal transduction ultimately leading to skin photoaging and even skin cancer.
 ...
PMID:AMP-activated protein kinase contributes to UV- and H2O2-induced apoptosis in human skin keratinocytes. 2987 10

AMP-activated protein kinase (AMPK), an evolutionarily conserved serine/threonine protein kinase, serves as an energy sensor in all eukaryotic cells. Recent findings suggest that AMPK activation strongly suppresses cell proliferation and induces cell apoptosis in a variety of cancer cells. Our study demonstrated that chemopreventive agent curcumin strongly activates AMPK in a p38-dependent manner in CaOV3 ovarian cancer cells. Pretreatment of cells with compound C (AMPK inhibitor) and SB203580 (p38 inhibitor) attenuates curcumin-induced cell death. We also observed that curcumin induces p53 phosphorylation (Ser 15) and both compound C and SB203580 pretreatment inhibit p53 phosphorylation. Collectively, our data suggest that AMPK is a new molecular target of curcumin and AMPK activation partially contributes to the cytotoxic effect of curcumin in ovarian cancer cells.
 ...
PMID:AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells. 1902 Jul 41

Although p73alpha induces many of the same cellular events as p53, it is structurally distinct from p53 in that it possesses a unique COOH-terminal domain. To dissect the function of this domain, we performed yeast two-hybrid screening of a HeLa cDNA library using residues 552-636 of p73alpha as bait. Among the clones that showed a specific interaction with p73alpha was AMP-activated protein kinase alpha (AMPKalpha). Additional yeast two-hybrid assays indicated that the betagamma-binding domain of AMPKalpha is critical for the interaction with p73alpha. The interaction was further confirmed in vitro by glutathione S-transferase pull-down, and in vivo by immunoprecipitation and immunofluorescence microscopy. Transient coexpression of AMPKalpha resulted in downregulation of the effect of p73alpha, but not of p53, on various p53-responsive promoters. Chromatin immunoprecipitation indicated p73alpha-dependent recruitment of AMPKalpha to the p21WAF1 promoter. Treatment with 5-aminoimidazole-4-carboxamide ribonucleotide, an agonist of AMPKalpha, and expression of dominant-negative versions of AMPKalpha revealed that the repression of p73alpha was independent of AMPKalpha kinase activity. In addition, cisplatin-induced growth repression was impaired when AMPKalpha was overexpressed. Upon the knock down of AMPKalpha by siRNA, the induction of p21WAF1 by p73alpha was significantly increased. Taken together, these data indicate that AMPKalpha specifically regulates p73alpha by a direct interaction without affecting its phosphorylation status. From these data, we speculate that AMPKalpha may provide a molecular clue to understand the repressive role of the C-terminus of p73alpha in transcription and DNA damage response.
 ...
PMID:Kinase activity-independent suppression of p73alpha by AMP-activated kinase alpha (AMPKalpha). 1907 40

p53 is a tumor suppressor protein that also plays a role in regulating aerobic metabolism. Since skeletal muscle is a major source of whole body aerobic respiration, it is important to delineate the effects of p53 on muscle metabolism. In p53 knockout (KO) mice, we observed diminished mitochondrial content in mixed muscle and lowered peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator (PGC)-1alpha protein levels in gastrocnemius muscle. In intermyofibrillar (IMF) mitochondria, lack of p53 was associated with reduced respiration and elevated reactive oxygen species production. Permeability transition pore kinetics remained unchanged; however, IMF mitochondrial cytochrome c release was reduced and DNA fragmentation was lowered, illustrating a resistance to mitochondrially driven apoptosis in muscle of KO mice. p53-null animals displayed similar muscle strength but greater fatigability and less locomotory endurance than wild-type (WT) animals. Surprisingly, the adaptive responses in mitochondrial content to running were similar in WT and KO mice. Thus p53 may be important, but not necessary, for exercise-induced mitochondrial biogenesis. In WT animals, acute muscle contractions induced the phosphorylation of p53 in concert with increased activation of upstream kinases AMP-activated protein kinase and p38, indicating a pathway through which p53 may initiate mitochondrial biogenesis in response to contractile activity. These data illustrate a novel role for p53 in maintaining mitochondrial biogenesis, apoptosis, and performance in skeletal muscle.
 ...
PMID:Role of p53 in mitochondrial biogenesis and apoptosis in skeletal muscle. 1910 83

AMP-activated protein kinase (AMPK) serves as a fuel-sensing enzyme that is activated by binding of AMP and subsequent phophorylation by upstream kinases such as the tumor suppressor LKB1, when cells sense an increase in the ratio of AMP to ATP. Acute activation of AMPK stimulates fatty acid oxidation to generate more ATP and simultaneously inhibits ATP-consuming processes including fatty acid and protein syntheses, thereby preserving energy for acute cell-surviving program, whereas chronic activation leads to inhibition of cell growth. The goal of the present study is to explore the mechanisms by which AMPK regulates cell growth. Toward this end, we established stable cell lines by introducing a dominant-negative mutant of AMPK alpha1 subunit or its shRNA into the prostate cancer C4-2 cells and other cells, or wild type LKB1 into the lung adenocarcinoma A549 and breast MB-MDA-231 cancer cells, both of which lack functional LKB1. Our results showed that the inhibition of AMPK accelerated cell proliferation and promoted malignant behavior such as increased cell migration and anchorage-independent growth. This was associated with decreased G1 population, downregulation of p53 and p21, and upregulation of S6K, IGF-1 and IGF1R. Conversely, treatment of the C4-2 cells with 5-aminoimidazole-4-carboxamide 1-D-ribonucleoside (AICAR), a prototypical AMPK activator, caused opposite changes. In addition, our study using microarray and RT-PCR revealed that AMPK regulated gene expression involved in tumor cell growth and survival. Thus, our study provides novel insights into the mechanisms of AMPK action in cancer cells and presents AMPK as an ideal drug target for cancer therapy.
 ...
PMID:Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells. 1934 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>