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)

Apoptosis (genetically programmed cell death) plays a key role in human physiology and pathogenesis of various diseases, including cancer. A suicide of cell can be initiated by many different factors, but activation of caspases, which are a special class of proteolytic enzymes, is always involved in this process. Activation of caspases may be achieved by several molecular pathways: the best known stimuli triggering caspase cascade are stimulation of Fas or TNF receptors, release of cytochrome c from the cellular mitochondria and exposure to granzymes, which are secreted by cytotoxic T cells. Activated caspases digest many cellular proteins responsible for cell cycle regulation (e.g. RB, MDM2), DNA damage recognition and repair (e.g. DNA-PK, P53, PARP), and regulation of the cellular structure (e.g. actin and lamins). All these functional and structural protein modifications lead directly to apoptosis. Further research on the mechanisms controlling caspase activity and the modes of action will provide better insight into pathogenesis of cancer and other disorders. It may be even the first step to design new and more efficient methods of conventional tumor treatment or gene therapy.
 ...
PMID:[Caspases and apoptosis: die and let live]. 1204 4

Tumor necrosis factor alpha (TNF alpha) plays a role in mammalian ovarian follicular development, steroidogenesis, ovulation, luteolysis, and atresia, but the exact mechanism of TNF alpha action is not completely understood. Induction of apoptosis and suppression of steroidogenesis by TNF alpha in primary preovulatory rat and human granulosa cells, as well as, in human granulosa cells immortalized by mutated p53, were characterized in the present work. Dexamethasone (Dex) and hydrocortisone efficiently suppressed TNF alpha-induced apoptosis in granulosa cells. TNF alpha dramatically reduced intracellular levels of Bcl-2, while Dex abrogated this reduction. TNF alpha reduced considerably intracellular levels of StAR protein, a key regulating factor in steroidogenesis. This reduction can be explained only in part by elimination of cells through apoptosis, since loss of steroidogenic capacity was much higher and faster than the rate and extent of loss of cell viability induced by TNF alpha, suggesting independent mechanisms for TNF alpha-induction of apoptosis and TNF alpha-suppression of steroidogenesis.
 ...
PMID:Induction of apoptosis in granulosa cells by TNF alpha and its attenuation by glucocorticoids involve modulation of Bcl-2. 1205 39

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, selectively induce apoptosis in various transformed cell lines but not in almost-normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2 and 2 decoy receptors, TRAIL-R3 and TRAIL-R4. However, the determining factors of the sensitivity to TRAIL-induced apoptosis are not clearly understood. Herein, we investigated the expression of TRAIL-R, c-FLIP, FADD-like interleukin-1beta-converting enzyme inhibitory protein, and TRAIL-induced apoptosis in human hepatocellular carcinoma (HCC) cell lines. Seven of ten HCC cell lines showed resistance to TRAIL-induced apoptosis and five of seven TRAIL-resistant cell lines became sensitive to TRAIL by co-treatment with cycloheximide. In HCC cell lines, their TRAIL resistance did not correlate with the basal expression level of TRAIL receptors or c-FLIP, however, in human tissues, TRAIL-R1 and TRAIL-R2 expressions were notably decreased compared to normal counterpart. Cisplatin showed synergistic effect on TRAIL-induced apoptosis in most HCC cell lines regardless of their p53 status and TRAIL-R1 was induced by cisplatin treatment in certain cell lines. Inhibition of nuclear factor K B (NF-kappaB) by SN50, a peptide inhibitor of NF-KB activity, had no effect on TRAIL-induced apoptosis in HCC cells. These results suggest that (a) the majority of human HCC cell lines are resistant to TRAIL-induced apoptosis and cycloheximide-sensitive short-lived antiapoptotic molecule(s) is responsible for this resistance, (b) the expression of TRAIL-R1 and TRAIL-R2 is reduced in HCC tissues, and the increased expression of TRAIL-R1 may be a mechanism of cisplatininduced sensitization to TRAIL-induced apoptosis in some HCC cells, and (c) the activation of NF-kappaB may not be involved in the TRAIL resistance of HCC cells
 ...
PMID:Human hepatocellular carcinoma cells resist to TRAIL-induced apoptosis, and the resistance is abolished by cisplatin. 1208 86

This paper lists the genotype frequencies of 50 polymorphisms of 37 genes (ALDH2, ADRB2, ADRB3, COMT, CD36, CXCR2, CCND1, COX2, CYP2A6, CYP17, CYP19, IGF1, IL-1A, IL-1B, IL-1RN, IL-1R1, IL-6, IL-8, IL-10, LEP, Le, L-myc, MPO, MTR, MTHFR, MAO-A, NQO1, OGG1, p53, p73, Se, SRD5A2, TGF-B, TNF-A, TNF-B, XPD, and XRCC1) and 6 sets of combined genotype frequencies for 241 non-cancer Japanese outpatients. Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers, 15 polymorphisms (CD36 A52C, CXCR2 C785T, CCND1 G870A, IGF1 C/T at intron 2 and G2502T, IL-1A 46-bp VNTR, IL-1R1 C-116T, IL-6 Ins/Del 17C, IL-8 A-278T and C74T, IL- 10 T-819C, LEP A-2548G, SRD5A2 2-bp VNTR, XPD Lys751Gln, and XRCC1 Arg399Gln) and six sets of combined genotype frequencies (IL-1B C-31T and IL-1A C-889T, IL-1B C-31T and IL-1RN 86-bp VNTR, IL-1B C-31T and IL-1R1 C-116T, TNF-A G-308A and TNF-B A252G, SRD5A2 Val89Leu and 2-bp VNTR, and XRCC1 Arg399Gln and XPD Lys751Gln) were reported in this paper for the first time for Japanese. Although microarray technology will produce this kind of information in near future, this is the first document that reports the genotype/allele frequencies among Japanese for an archival purpose.
 ...
PMID:Genotype frequencies of 50 polymorphisms for 241 Japanese non-cancer patients. 1216 25

Adenoviruses (Ads) cause acute and persistent infections. Alike the much more complex herpesviruses, Ads encode numerous immunomodulatory functions. About a third of the viral genome is devoted to counteract both the innate and the adaptive antiviral immune response. Immediately upon infection, E1A blocks interferon-induced gene expression and the VA-RNA inhibits interferon-induced PKR activity. At the same time, E1A reprograms the cell for DNA synthesis and induces the intrinsic cellular apoptosis program that is interrupted by E1B/19K and E1B/55K proteins, the latter inhibits p53-mediated apoptosis. Most other viral stealth functions are encoded by a separate transcription units, E3. Several E3 products prevent death receptor-mediated apoptosis. E3/14.7K seems to interfere with the cytolytic and pro-inflammatory activities of TNF while E3/10.4K and 14.5K proteins remove Fas and TRAIL receptors from the cell surface by inducing their degradation in lysosomes. These and other functions that may afect granule-mediated cell death might drastically limit lysis by NK cells and cytotoxic T cells (CTL). Moreover, Ads interfere with recognition of infected cell by CTL. The paradigmatic E3/19K protein subverts antigen presentation by MHC class I molecules by inhibiting their transport to the cell surface. In concert, these viral countermeasures ensure prolonged survival in the infected host and, as a consequence, facilitate transmission. Elucidating the molecular mechanisms of Ad-mediated immune evasion has stimulated corresponding research on other viruses. This knowledge will also be instrumental for designing better vectors for gene therapy and vaccination, and may lead to a more rational treatment of life-threatening Ad infections, e.g. in transplantation patients.
 ...
PMID:Subversion of host defense mechanisms by adenoviruses. 1222 14

Aging enhances apoptosis of hepatocytes under normal physiological conditions and increases the susceptibility to apoptosis of hepatocytes, whereas chronic calorie restriction (CR) suppresses the age-enhanced susceptibility to apoptosis. To clarify the subcellular mechanisms of age-associated dysregulation of apoptosis and the effects of CR, we analyzed the expression of genes promoting apoptosis (p53, Fas receptor, Fas ligand, TNF receptor 1, TNFalpha, Bax, TGF beta 1) and genes preventing apoptosis (Bcl-2 and Bcl-XL) in the livers of 3-, 6-, 15-, and 24-month-old male F344 rats that were either fed ad libitum or subjected to a 30% reduction in food intake (CR). After the age of 6 months, expression of p53, Fas receptor, Fas ligand, and TNFalpha mRNAs was up-regulated with aging. CR suppressed this age-enhanced p53 and Fas receptor mRNA expression, but expression of the other genes was not altered significantly by aging or CR. Expression of Fas receptor in hepatocytes, as detected immunohistochemically, increased with age, but CR suppressed age-accelerated Fas receptor expression. Our findings suggest that TNF ligand/TNF receptor family signaling, particularly Fas receptor expression, is important in age- and CR-modulated apoptosis of hepatocytes. Hepatocytes that were immunoreactive for p53 had slightly increased with aging, suggesting that p53 may mediate the age-enhanced up-regulation of Fas receptor in hepatocytes.
 ...
PMID:Impact of aging and life-long calorie restriction on expression of apoptosis-related genes in male F344 rat liver. 1242 91

TNF-related apoptosis-inducing ligand (TRAIL/Apo- 2L), a newly identified member of the TNF family promotes apoptosis by binding to the transmembrane receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL known to activate NF-kappaB in number of tumor cells including A549 (wt p53) and NCI-H1299 (null p53) lung cancer cells exerts relatively selective cytotoxic affects to the human tumor cell lines without much effect on the normal cells. We set out to identify an agent that would sensitize lung cancer cells to TRAIL-induced apoptosis through inhibition of NF-kappaB activation. We found that triptolide, an oxygenated diterpene extracted and purified from the Chinese herb Tripterygium wilfordii sensitized A549 and NCI-H1299 cells to TRAIL-induced apoptosis through inhibition of NF-kappaB activation. Pretreatment with MG132 which is a well-known NF-kappaB inhibitor by blocking degradation of IkappaBalpha also greatly sensitized lung cancer cells to TRAIL-induced apoptosis. Triptolide did not block DNA binding of NF-kappaB activated by TRAIL as in the case of TNF-alpha. It has been already proven that triptolide blocks transactivation of p65 which plays a key role in NF-kappaB activation. These observations suggest that triptolide may be a potentially useful drug to enhance TRAIL-induced tumor killing in lung cancer.
 ...
PMID:Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-kappaB activation. 1252 88

Melanoma cells can undergo self-destruction via programmed cell death, i.e. apoptosis. In these tumours, the molecular components of apoptosis include positive (apoptotic) and negative (anti-apoptotic) regulators. The former include p53, Bid, Noxa, PUMA, Bax, TNF, TRAIL, Fas/FasL, PITSLRE, interferons, and c-KIT/SCF. The latter include Bcl-2, Bcl-X(L), Mcl-1, NF-(K)B, survivin, livin, and ML-IAP. Alternatively, some molecules such as TRAF-2, c-Myc, endothelins, and integrins may have either pro- or anti-apoptotic effects. Some of these molecules are of potential therapeutic use, such as: (1) p53, which influences resistance to chemotherapy; (2) Mcl-1 and Bcl-X(L), which can override apoptosis; (3) TRAIL, which has selective fatal effects on tumour cells; (4) NF-(K)B, which when downregulated sensitizes cells to TRAIL and TNF; (5) the PITSLRE kinases, whose alteration appears to result in Fas resistance; (6) interferons, which sensitize cells to other factors; and (7) survivin and other IAPs that inhibit apoptosis. This review summarizes the state of current knowledge about the key molecular components and mechanisms of apoptosis in melanoma, discusses potential therapeutic ramifications, and provides directions for future research.
 ...
PMID:Apoptosis and melanoma: molecular mechanisms. 1451 53

Allele frequencies are rather constant among different ethnic groups in many genetic polymorphisms, but some polymorphisms vary in the allele frequency depending on the time when the germ-line base exchanges occurred in the history of humans and on the adaptability of the phenotypes to given environment. This review documented the allele frequencies of polymorphisms pertaining to cancer risk for Japanese, Koreans, and Chinese. Twenty-five polymorphisms of 21 genes whose allele frequencies were available for at least two out of the three ethnic groups were selected. They were ALDH2 Glu487Lys, COMT Val158Met, CYP1A1 MspI and Val/Ile, CYP1B1 Leu432Val, CYP2E1 RsaI, CYP17 T-34C, ER C975G, GSTM1, GSTT1, GSTP1 Ile105Val, IL-1B C-511T, IL-1RN 86-bp VNTR (variable number of tandem repeats), MTHFR C677T and A1298C, NAT1, NAT2, NQO1 Pro187Ser, OGG1 Ser326Cys, p21 Ser31Arg, p53 Arg72Pro, TNF-A G-308A and G-238A, and XRCC1 Arg194Trp and Arg399Gln. The allele frequencies were found for 24 in Japanese, 16 in Koreans, and 24 in Chinese. All of the polymorphisms had similar allele frequencies for these ethnic groups, except the following polymorphisms; ALDH2 Glu487Lys whose Lys allele was more common for Japanese and Taiwanese, COMT Val158Met whose Met allele was more common for Japanese, and NAT2 rapid/slow whose slow alleles were more common for Chinese. When compared with the allele frequencies among Caucasians, the following minor alleles were more frequent among Japanese/Koreans/Chinese; ALDH2 478Lys, CYP1A1 m1 and m2, CYP2E1 c2, ER 975G, GSTT1 null, NAT1 *10, NQO1 187Ser, OGG1 326Cys, p21 31Arg, and XRCC1 194Trp, and less frequent in COMT 158Met, GST-P1 105Val, IL-1RN non-4R, MTHFR 1298C, and TNF-A -308A. The differences in genetic background may affect the impact on the lifestyle factors and/or genotypes examined in epidemiological studies. However, the influences of the variations in the allele frequency seemed to be limited among Japanese, Koreans, and Chinese. The substantial differences in the allele frequency from Caucasians could modify the influences of lifestyle factors and polymorphism genotypes, resulting in the inconsistent results of epidemiologic studies.
 ...
PMID:Allele Frequencies of 25 Polymorphisms Pertaining to Cancer Risk for Japanese, Koreans and Chinese. 1271 76

Inactivation of p53 has been implicated in many types of tumors particularly in non-small cell lung carcinoma, one of the most common cancers in which p53 mutation has been frequently identified. The aim of this study was to investigate the influence of p53 status on the regulation of tumor susceptibility to specific CTL-mediated cell death. For this purpose, we used a cytotoxic T lymphocyte clone, Heu127, able to lyse the human autologous lung carcinoma cell line, IGR-Heu, in a HLA-A2-restricted manner. Direct genomic DNA sequencing revealed that IGR-Heu expresses a mutated p53 at codon 132 of the exon 5 which results in the loss of p53 capacity to induce the expression of the p53-regulated gene product p21(waf/CIP1). Initial experiments demonstrated that IGR-Heu was resistant to Fas, TNF, and TRAIL apoptotic pathways. This correlated with the lack of p55 TNFRI, Fas, DR4, and DR5 expression. The effect of wild-type (wt) p53 restoration on the sensitization of IGR-Heu to autologous CTL clone lysis was investigated following infection of the tumor cell line with a recombinant adenovirus encoding the wt p53 (Adwtp53). We demonstrate that the restoration of wt p53 expression and function resulted in a significant potentiation of target cell susceptibility to CTL-mediated lysis. The wt p53-induced optimization of tumor cell killing by specific CTL involves at least in part Fas-mediated pathway via induction of CD95 expression by tumor cells but does not appear to interfere with granzyme B cytotoxic pathway.
 ...
PMID:Potentiation of a tumor cell susceptibility to autologous CTL killing by restoration of wild-type p53 function. 1279 18


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