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)

Ubiquitin carboxy terminal hydrolase-L1 (UCH-L1) belongs to the UCH proteases family that deubiquitinates ubiquitin-protein conjugates in the ubiquitin-proteasome system. Previous research showed that UCH-L1 was expressed in mouse retinal cells and testicular germ cells, and its function was associated with apoptosis. But it is still unclear whether UCH-L1 is concerned with apoptosis in tumor cells. In order to clarify the role of UCH-L1 in tumor cells, multi-drug resistance (MDR) human breast carcinoma cell line MCF7/Adr, that expresses relatively high UCH-L1, and its parental cell line MCF7, that expresses relatively low UCH-L1, were chosen for this study. We transfected pcDNA3.1-UCH-L1 plasmid and UCH-L1 siRNA into MCF7 and MCF7/Adr cells, respectively. Using 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, western blot, Hoechst 33258 staining assay and flow cytometry, we found that over-expression of UCH-L1 in MCF7 cells induced apoptosis. On the other hand, silencing of UCH-L1 in MCF7/Adr cells led to the opposite effect. Moreover, to explore the mechanism underling these observations, we further investigated the expression of phospho-Akt and its downstream signal phospho-IkB-alpha and other signal molecules including Fas, Fas-L, Trail, DR4, DR5, Bax, cytochrome C, active caspase-3, phospho-p53, phospho-Mdm-2, Bcl-2, Bcl-xL, p21 and p27. The results indicated that the process of apoptosis triggered by UCH-L1 is, at least in part, probably through Phosphoinositide 3-kinase (PI3K)/Akt signal pathway. Our findings suggest that modulating the ubiquitination and deubiquitination pathway could be a novel method for tumor therapy.
 ...
PMID:Over-expression of ubiquitin carboxy terminal hydrolase-L1 induces apoptosis in breast cancer cells. 1894 67

Longevity in yeast, nematodes, fruit flies and mice is affected by mutations in the insulin/IGF-1 or homologous pathways. Studies on long-living people revealed some associations between genetic variants of the insulin/IGF-1 pathway and longevity. Here, we review such investigations, and we will report human longevity association studies regarding the variability of genes which modulate lifespan in model organisms by interacting with the insulin/IGF-1 pathway. These studies will be presented in three groups: (1) insulin/IGF-1 pathway transcriptional target, superoxide dismutase 2, heat shock protein, cytochrome p450 isoenzymes, glutathione transferases; (2) insulin/IGF-1 pathway accessory transduction proteins H-Ras, p66Shc; and (3) longevity pathways that converge on the insulin/IGF-1 pathway (Klotho, p53, Sirtuins, TGF-beta). The data reported support the notion that the insulin/IGF-1 pathway drives an evolutionarily conserved network that regulates lifespan and affects longevity across species.
 ...
PMID:Genetic polymorphism in long-lived people: cues for the presence of an insulin/IGF-pathway-dependent network affecting human longevity. 1902 25

Apoptotic myocyte cell death, diastolic dysfunction, and progressive deterioration in left ventricular pump function characterize the clinical course of diabetic cardiomyopathy. A key question concerns the mechanism(s) by which hyperglycemia (HG) transmits danger signals in cardiac muscle cells. The growth factor adapter protein p66ShcA is a genetic determinant of longevity, which controls mitochondrial metabolism and cellular responses to oxidative stress. Here we demonstrate that interventions which attenuate or prevent HG-induced phosphorylation at critical position 36 Ser residue (phospho-Ser36) inhibit the redox function of p66ShcA and promote the survival phenotype. Adult rat ventricular myocytes obtained by enzymatic dissociation were transduced with mutant-36 p66ShcA (mu-36) dominant-negative expression vector and plated in serum-free media containing 5 or 25 mM glucose. At HG, adult rat ventricular myocytes exhibit a marked increase in reactive oxygen species production, upregulation of phospho-Ser36, collapse of mitochondrial transmembrane potential, and increased formation of p66ShcA/cytochrome-c complexes. These indexes of oxidative stress were accompanied by a 40% increase in apoptosis and the upregulation of cleaved caspase-3 and the apoptosis-related proteins p53 and Bax. To test whether p66ShcA functions as a redox-sensitive molecular switch in vivo, we examined the hearts of male Akita diabetic nonobese (C57BL/6J) mice. Western blot analysis detected the upregulation of phospho-Ser36, the translocation of p66ShcA to mitochondria, and the formation of p66ShcA/cytochrome-c complexes. Conversely, the correction of HG by recombinant adeno-associated viral delivery of leptin reversed these alterations. We conclude that p66ShcA is a molecular switch whose redox function is turned on by phospho-Ser36 and turned off by interventions that prevent this modification.
 ...
PMID:Inhibition of p66ShcA redox activity in cardiac muscle cells attenuates hyperglycemia-induced oxidative stress and apoptosis. 1906 Jan 30

Depletion of intracellular zinc with N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) induces protein synthesis-dependent apoptosis. In this study, we examined the requirement for p53 as an upstream transcription factor in TPEN-induced neuronal apoptosis. Chemical or genetic blockade of p53 markedly attenuated TPEN-induced neuronal apoptosis, while the stability and activity of p53 were increased by TPEN. In addition, expression of proapoptotic genes, PUMA and NOXA, and activation of caspase-11 were increased by TPEN in a p53-dependent manner. Inhibition of p53 blocked cytochrome C release from mitochondria to cytosol and prevented caspase-3 activation. Therefore, p53 may be an essential regulatory factor for TPEN-induced neuronal apoptosis.
 ...
PMID:Essential role of p53 in TPEN-induced neuronal apoptosis. 1936 7

Strategies to induce p53 activation in tumors that retain wild-type p53 are promising for cancer therapy. Nutlin is a potent and selective pharmacological MDM2 inhibitor that competitively binds to its p53-binding pocket, thereby leading to non-genotoxic p53 stabilization and activation of growth arrest and apoptosis pathways. Nutlin-induced apoptosis is thought to occur via p53's transcriptional program. Here we report that the transcription-independent mitochondrial p53 program plays an important role in Nutlin-induced p53-mediated tumor cell death. Aside from nuclear stabilization, Nutlin causes cytoplasmic p53 accumulation and translocation to mitochondria. Monoubiquitinated p53, originating from a distinct cytoplasmic pool, is the preferred p53 species that translocates to mitochondria in response to stress. Nutlin does not interfere with MDM2's ability to monoubiquitinate p53, due to the fact that MDM2-p53 complexes are only partially disrupted and that Nutlin-stabilized MDM2 retains its E3 ubiquitin ligase activity. Nutlin-induced mitochondrial p53 translocation is rapid and associated with cytochrome C release that precedes induction of p53 target genes. Specific inhibition of mitochondrial p53 translocation by Pifithrin mu reduces the apoptotic Nutlin response by 2.5-fold, underlining the significance of p53's mitochondrial program in Nutlin-induced apoptosis. Surprisingly, blocking the transcriptional arm of p53, either via alpha-Amanitin or the p53-specific transcriptional inhibitor Pifithrin alpha, not only fails to inhibit, but greatly potentiates Nutlin-induced apoptosis. In sum, the direct mitochondrial program is a major mechanism in Nutlin-induced p53-mediated apoptosis. Moreover, at least in some tumors the transcriptional p53 activities in net balance not only are dispensable for the apoptotic Nutlin response, but appear to actively block its therapeutic effect.
 ...
PMID:The transcription-independent mitochondrial p53 program is a major contributor to nutlin-induced apoptosis in tumor cells. 1944 34

In addition to well-documented mood-stabilizing effects, lithium can be used in the treatment of acute brain injuries (ischemia) and chronic (neurodegenerative) diseases. Recent in vitro and in vivo studies reveal that the long-term treatment with lithium up-regulates cell survival molecules (Bcl-2, cAMP-responsive element binding protein, GRP 78, brain-derived neurotrophic factor, Hsp70) and down-regulates pro-apoptotic activities (e.g., excitotoxicity, p53, Bax, caspase, cytochrome C release, beta-amyloid peptide production and tau hyperphosphorylation) thus preventing or even reversing the neuronal cell death and neurogenesis retardation.
 ...
PMID:[Neurobiology of lithium]. 1942 90

To investigate whether simultaneous exposure to acrylamide (ACR) and long-term dietary corn oil induces colon cancer by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis in rats. Male Sprague-Dawley rats were given intraperitoneal injections of ACR at dose of 10 mg/kgbw and diets supplemented with 10% corn oil for 8 wks; and then rats were still fed with diets supplemented with 10% oil for other 48 wks. Colonic aberrant crypt foci (ACF) and tumors, including adenomas and carcinomas, were examined at 12, 24, 36, 48 week post ACR-exposure. Colonic apoptosis and cell proliferation, expression of Wild type (wt) p53, Bcl-2, Bax and caspase-3, were detected at 48 week post ACR-exposure. ACF was found at 12 week and colon cancer invasion was found at 48 week in ACR rats on long-term dietary corn oil. Apoptosis was decreased and cell proliferation was increased in colonic mucosa in ACR-treated rats on dietary corn oil compared to vehicle rats on basal diet (P < 0.05). In ACR rats on dietary corn oil, mitochondrial wt p53 was significantly inhibited through decreased mitochondrial localization of wt p53 and increased cytosolic p53, resulting in the up-regulation of Bcl-2 and the down-regulation of Bax in the mitochondria, also inhibition of the release of cytochrome-c from the mitochondria into the cytosol and protein level of caspase-3 (P < 0.05). Results suggest that simultaneous exposure to ACR and long-term dietary corn oil induces development of colon cancer partly by inhibiting the tumor suppressor gene p53-mediated mitochondria-dependent apoptosis.
 ...
PMID:Simultaneous exposure to dietary acrylamide and corn oil developed carcinogenesis through cell proliferation and inhibition of apoptosis by regulating p53-mediated mitochondria-dependent signaling pathway. 1945 32

Limonoids from the neem tree (Azadirachta indica) have attracted considerable research attention for their cytotoxicity against human cancer cell lines. However, the antiproliferative and apoptosis inducing effects of neem limonoids have not been tested in animal tumour models. The present study was therefore designed to evaluate the relative chemopreventive potential of the neem limonoids azadirachtin and nimbolide in the hamster buccal pouch (HBP) carcinogenesis model by analyzing the expression of proliferating cell nuclear antigen (PCNA), p21(waf1), cyclin D1, glutathione S-transferase pi (GST-P), NF-kappaB, inhibitor of kappaB (IkappaB), p53, Fas, Bcl-2, Bax, Bid, Apaf-1, cytochrome C, survivin, caspases-3, -6, -8 and -9, and poly(ADP-ribose) polymerase (PARP) by RT-PCR, immunohistochemical, and Western blot analyses. The results provide compelling evidence that azadirachtin and nimbolide mediate their antiproliferative effects by downregulating proteins involved in cell cycle progression and transduce apoptosis by both the intrinsic and extrinsic pathways. On a comparative basis, nimbolide was found to be a more potent antiproliferative and apoptosis inducing agent and offers promise as a candidate agent in multitargeted prevention and treatment of cancer.
 ...
PMID:The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis. 1945 12

MDM4 is a key regulator of p53, whose biological activities depend on both transcriptional activity and transcription-independent mitochondrial functions. MDM4 binds to p53 and blocks its transcriptional activity; however, the main cytoplasmic localization of MDM4 might also imply a regulation of p53-mitochondrial function. Here, we show that MDM4 stably localizes at the mitochondria, in which it (i) binds BCL2, (ii) facilitates mitochondrial localization of p53 phosphorylated at Ser46 (p53Ser46(P)) and (iii) promotes binding between p53Ser46(P) and BCL2, release of cytochrome C and apoptosis. In agreement with these observations, MDM4 reduction by RNA interference increases resistance to DNA-damage-induced apoptosis in a p53-dependent manner and independently of transcription. Consistent with these findings, a significant downregulation of MDM4 expression associates with cisplatin resistance in human ovarian cancers, and MDM4 modulation affects cisplatin sensitivity of ovarian cancer cells. These data define a new localization and function of MDM4 that, by acting as a docking site for p53Ser46(P) to BCL2, facilitates the p53-mediated intrinsic-apoptotic pathway. Overall, our results point to MDM4 as a double-faced regulator of p53.
 ...
PMID:MDM4 (MDMX) localizes at the mitochondria and facilitates the p53-mediated intrinsic-apoptotic pathway. 1952 40

T-2 toxin is the most toxic trichothecene and both humans and animals suffer from several pathological conditions after consumption of foodstuffs contaminated with trichothecenes. We investigated the molecular mechanism of T-2 toxin induced cytotoxicity and cell death in HeLa cells. T-2 toxin at LC50 of 10 ng/ml caused time dependent increase in cytotoxicity as assessed by dye uptake, lactatedehydrogenase leakage and MTT assay. The toxin caused generation of reactive oxygen species as early as 30 min followed by significant depletion of glutathione levels and increased lipid peroxidation. The results indicate oxidative stress as underlying mechanism of cytotoxicity. Single stranded DNA damage after T-2 treatment was observed as early as 2 and 4h by DNA diffusion assay. The cells exhibited apoptotic morphology like condensed chromatin and nuclear fragmentation after 4h of treatment. Downstream of T-2 induced oxidative stress and DNA damage a time dependent increase in expression level of p53 protein was observed. The increase in Bax/Bcl2 ratio indicated shift in response, in favour of apoptotic process in T-2 toxin treated cells. Western blot analysis showed increase in levels of mitochondrial apoptogenic factors Bax, Bcl-2, cytochrome-c followed by activation of caspases-9, -3 and -7 leading to DNA fragmentation and apoptosis. In addition to caspase-dependent pathway, our results showed involvement of caspase-independent AIF pathway in T-2 induced apoptosis. Broad spectrum caspase inhibitor z-VAD-fmk could partially protect the cells from DNA damage but could not inhibit AIF induced oligonucleosomal DNA fragmentation beyond 4 h. Results of the study clearly show that oxidative stress is the underlying mechanism by which T-2 toxin causes DNA damage and apoptosis.
 ...
PMID:Oxidative stress induction by T-2 toxin causes DNA damage and triggers apoptosis via caspase pathway in human cervical cancer cells. 1952 37


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