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)

Poly(ADP-ribose) is formed in possibly all multicellular organisms by a familiy of poly(ADP-ribose) polymerases (PARPs). PARP-1, the best understood and until recently the only known member of this family, is a DNA damage signal protein catalyzing its automodification with multiple, variably sized ADP-ribose polymers that may contain up to 200 residues and several branching points. Through these polymers, PARP-1 can interact noncovalently with other proteins and alter their functions. Here we report the discovery of a poly(ADP-ribose)-binding sequence motif in several important DNA damage checkpoint proteins. The 20-amino acid motif contains two conserved regions: (i) a cluster rich in basic amino acids and (ii) a pattern of hydrophobic amino acids interspersed with basic residues. Using a combination of alanine scanning, polymer blot analysis, and photoaffinity labeling, we have identified poly(ADP-ribose)-binding sites in the following proteins: p53, p21(CIP1/WAF1), xeroderma pigmentosum group A complementing protein, MSH6, DNA ligase III, XRCC1, DNA polymerase epsilon, DNA-PK(CS), Ku70, NF-kappaB, inducible nitric-oxide synthase, caspase-activated DNase, and telomerase. The poly(ADP-ribose)-binding motif was found to overlap with five important functional domains responsible for (i) protein-protein interactions, (ii) DNA binding, (iii) nuclear localization, (iv) nuclear export, and (v) protein degradation. Thus, PARPs may target specific signal network proteins via poly(ADP-ribose) and regulate their domain functions.
 ...
PMID:Poly(ADP-ribose) binds to specific domains in DNA damage checkpoint proteins. 1101 34

Dracorhodin perchlorate, an anthocyanin red pigment, induces human melanoma A375-S2 cell death through the apoptotic pathway. Caspase-3, -8, -9, and -10 inhibitors partially reversed the cell death induced by dracorhodin perchlorate. Caspase-3 and -8 were activated, followed by the degradation of caspase-3 substrates, the inhibitor of caspase-activated DNase, and poly-(ADP-ribose) polymerase. Dracorhodin perchlorate upregulated the expression ratio of Bax/Bcl-2 and significantly increased the expression of p53 and p21(WAF1) proteins. The cell death was partially reduced by the mitogen-activated protein kinase c-JUN NH2-terminal protein kinase (JNK MAPK) inhibitor (SP600125) and p38 MAPK inhibitor (SB 203580), while the MEK inhibitor (PD98059) augmented cell death; the drug induced sustained phosphorylation of JNK and p38 MAPK. Moreover, the Fas agonistic antibody CH-11 has a synergistic effect with dracorhodin perchlorate. The phoshatidylinositol 3-kinase (PI3-K) family inhibitor wortmanin and tyrosine kinase inhibitor genistein rescued the viability loss induced by dracohodin perchlorate. Taken together, dracorhodin perchlorate induces apoptosis in A375-S2 cells via accumulation of p53, alters the Bax/Bcl-2 ratio, and activates caspases and p38/JNK MAPKs.
 ...
PMID:Dracorhodin perchlorate induces A375-S2 cell apoptosis via accumulation of p53 and activation of caspases. 1568 74

Pseudolaric acid B is a major compound found in the bark of Pseudolarix kaempferi Gordon. In our study, pseudolaric acid B inhibited growth of human melanoma cells, A375-S2 in a time- and dose-dependent manner. A375-S2 cells treated with pseudolaric acid B showed typical characteristics of apoptosis including morphologic changes, DNA fragmentation, sub-diploid peak in flow cytometry, cleavage of poly-ADP ribose polymerase (PARP) and degradation of inhibitor of caspase-activated DNase (ICAD). P53 protein expression was upregulated while cells were arrested at the G2/M phase of the cell cycle. There was a decrease in the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins, whereas pro-apoptotic Bax was increased. The two classical caspase substrates, PARP and ICAD, were both decreased in a time-dependent manner, indicating the activation of downstream caspases.
 ...
PMID:Pseudolaric acid B induces apoptosis through p53 and Bax/Bcl-2 pathways in human melanoma A375-S2 cells. 1574 11

We have previously shown that DNA from dying tumor cells may be transferred to living cells via the uptake of apoptotic bodies and may contribute to tumor progression. DNA encoding H-ras(V12) and c-myc oncogenes may be transferred to the nucleus of the phagocyte but will only integrate and propagate in p53- and p21-deficient mouse embryonic fibroblasts, whereas normal cells are resistant to transformation. Here, we show that this protective mechanism (activation of p53 and p21 after uptake of apoptotic bodies) is dependent on DNA fragmentation, where inhibition of the caspase-activated DNase in the apoptotic cells, in conjunction with genetic ablation of lysosomal DNase II in the phagocytes, completely blocks p53 activation and consequently allows DNA replication of transferred DNA. We, therefore, suggest that there is a causal relationship between DNA degradation during apoptosis and p53 activation. In addition, we could further show that Chk2-/- cells were capable of replicating the hyg(R) gene taken up from engulfed apoptotic cells, suggesting involvement of the DNA damage response. These data show that the phagocytosing cell is sensing the degraded DNA within the apoptotic cell, hence preventing these genes from being replicated, probably through activation of the DNA damage response. We, therefore, hypothesize that DNase II together with the Chk2, p53, and p21 pathway form a genetic barrier blocking the replication of potentially harmful DNA introduced via apoptotic bodies, thereby preventing transformation and malignant development.
 ...
PMID:DNase II and the Chk2 DNA damage pathway form a genetic barrier blocking replication of horizontally transferred DNA. 1654 56

DNA fragmentation factor (DFF)/caspase-activated DNase (CAD) is responsible for DNA fragmentation, a hallmark event during apoptosis. Although DNA fragmentation is an evolutionarily conserved process across species, its biological function is not clearly understood. In this study, we constructed cell lines expressing a mutant ICAD (inhibitor of CAD) protein that is resistant to caspase cleavage and therefore constantly binds to DFF/CAD and inhibits DNA fragmentation. We found that irradiation of these cells led to increased chromosome aberrations and aneuploidy when compared with their parental controls. The increased chromosome instability is observed irrespective of cellular P53 status, suggesting that the effect of DFF/CAD is independent of P53. Inhibition of apoptotic DNA fragmentation resulted in increased clonogenic survival of irradiated cells and a delay in removal of cells with DNA damages induced by radiation, an effect similar to that in cells with p53 mutations. Consistent with DFF/CAD's effect on clonogenic survival, tumors established from cells deficient in DNA fragmentation showed enhanced growth in nude mice. Therefore, our results suggest that DFF/CAD plays an important and P53-independent role in maintaining chromosome stability and suppressing tumor development.
 ...
PMID:Apoptotic DNA fragmentation factor maintains chromosome stability in a P53-independent manner. 1661 42

Silibinin, derived from the milk thistle plant, Silybum marianum, has been traditionally used as an antihepatotoxic agent for the treatment of liver disease. Our preliminary study demonstrated that silibinin has protected rat cardiac myocytes against beta-adrenergic agonist isoproterenol-induced injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members. In this study, we investigate whether silibinin has anti-apoptotic effect on isoproterenol-treated rat cardiac myocytes. DNA damage, detected by the TUNEL and DNA fragmentation assay, was diminished after treatment of silibinin. Results of nitrite and Western blot assays showed that the amount of NO and the expression of iNOS were decreased after treatment with silibinin, while the expression of procaspase-3 and digestion of caspase-3 substrates, the inhibitor of caspase-activated DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP), were increased simultaneously. The DNA damage was reversed by down-regulation of p53 phosphorylation after treatment with silibinin. Result of flowcytometric analysis showed that the cell cycle was not affected, and the expression of cell cycle regulatory protein p21 also had no change. Consequently, silibinin protected cardiac myocytes against isoproterenol-induced DNA damage through caspase pathway and the expression of p53, but independent on regulation of cell cycle.
 ...
PMID:Silibinin protects rat cardiac myocyte from isoproterenol-induced DNA damage independent on regulation of cell cycle. 1694 6

Previously it was shown that horizontal DNA transfer between mammalian cells can occur through the uptake of apoptotic bodies, where genes from the apoptotic cells were transferred to neighbouring cells phagocytosing the apoptotic bodies. The regulation of this process is poorly understood. It was shown that the ability of cells as recipient of horizontally transferred DNA was enhanced by deficiency of p53 or p21. However, little is known with regard to the regulation of DNA from donor apoptotic cells. Here we report that the DNA fragmentation factor/caspase-activated DNase (DFF/CAD), which is the endonuclease responsible for DNA fragmentation during apoptosis, plays a significant role in regulation of horizontal DNA transfer. Cells with inhibited DFF/CAD function are poor donors for horizontal gene transfer (HGT) while their ability of being recipients of HGT is not affected.
 ...
PMID:Regulation of mammalian horizontal gene transfer by apoptotic DNA fragmentation. 1714 78

The aim of this study was to understand the role of tumor progression in the growth properties of tumor cells and their susceptibility to the cytotoxicity of chemotherapeutic drugs. A murine transplantable T cell lymphoma of spontaneous origin, designated as Dalton's lymphoma, was used as a model tumor for this investigation. Tumor cells were harvested from the early (5 days after tumor transplantation) and late tumor-bearing stages (17 days after tumor transplantation), with or without in-vivo administration of the chemotherapeutic drugs, cisplatin or doxorubicin. Tumor cells harvested at the late tumor-bearing stages showed a higher proliferative ability in vitro. Tumor progression was found to be associated with a decline in the tumor cytotoxicity of the chemotherapeutic drugs. Similar results were also obtained when tumor cells were cultured at low (10(5) cells/ml) and high (10(9) cells/ml) cell densities in vitro in medium alone or in one containing the chemotherapeutic drugs. An increase in the expression of heat shock protein (Hsp70), vascular endothelial growth factor, interleukin-2 receptor and interleukin-2 proteins along with an inhibition in the expression of caspase-activated DNase and p53 proteins was observed during the late tumor-bearing stage and also in the Dalton's lymphoma cells when cultured in vitro at a higher cell density. The ascitic fluid obtained from the late tumor-bearing stage and the culture supernatant of tumor cells incubated in vitro at high cell density showed high levels of cell growth-regulating cytokines: interleukin-1, interleukin-2, interferon-gamma, vascular endothelial growth factor, tumor growth factor-beta and interleukin-10. In-vivo administration of cisplatin in tumor-bearing mice at the late tumor-bearing stage did not alter the level of these cytokines in the ascitic fluid. In view of the results of this investigation, it is suggested that under high cellular density-associated environmental conditions the tumor cells alter their growth properties depending on an alteration in the expression of cell growth and apoptosis-regulating proteins. Tumor cells, thus, switch to a high level of proliferation, which renders them resistant to the cytotoxicity of chemotherapeutic drugs.
 ...
PMID:Effect of high cell density on the growth properties of tumor cells: a role in tumor cytotoxicity of chemotherapeutic drugs. 1789 12

Previously we have demonstrated that in-vivo growth of a murine T-cell lymphoma of spontaneous origin designated as Dalton's lymphoma (DL) shows sex dimorphism (J Rep Immunol 2005; 65:17-32). It remained unclear, however, if DL growth in female and male tumor-bearing hosts also shows a sex-dependent differential susceptibility to the antitumor action of cancer chemotherapeutic drugs. In this study we have demonstrated that in-vivo administration of anticancer drugs: cisplatin or doxorubicin to the DL-bearing host results in a sex-dependent different antitumor activity of the drugs, causing a sex dimorphism in the antitumor response of the drugs with respect to tumor growth inhibition. The antitumor effect of both drugs was found to be better in male tumor-bearing hosts compared with female tumor-bearing hosts. The study also shows that DL cells obtained from male and female tumor-bearing hosts display a differential growth response to following treatment with cisplatin in vitro. Cell growth regulatory proteins: interleukin-2, interferon-gamma, tumor growth factor-beta, p53, caspase-activated DNase, vascular endothelial growth factor, and interleukin-2 receptor were found to be involved in the observed sex-specific response of DL cells to the antitumor action of cisplatin. Moreover, gonadal hormones: androgen, estrogen, and their specific antagonists flutamide and tamoxifen were found to directly modulate the cytotoxicity of cisplatin against DL cells in vitro. This study, therefore, suggests for the first time that the efficacy of cancer chemotherapeutic may vary in a sex-specific manner in a host-bearing a T-cell lymphoma.
 ...
PMID:Sex dimorphism in antitumor response of chemotherapeutic drug cisplatin in a murine host-bearing a T-cell lymphoma. 1852 17

It has now been more than ten years since the discovery of the major apoptotic nuclease, DNA fragmentation factor (DFF), also known as caspase-activated DNase (CAD). Here we review the recent literature that has uncovered new insight into DFF's regulation, and both its positive and negative roles in human disease. Cells from mice deficient in DFF still undergo apoptotic death without significant cell-autonomous DNA degradation. Their corpses' genomes are subsequently degraded by lysosomal DNase II after phagocytosis. However,DFF-deficient mice are more susceptible to cancer. Indeed, several different cancers in humans are associated with defects in DFF expression and it has been proposed that DFF is a p53-independent tumor suppressor. Negative aspects of DFF expression include contributing to susceptibility to acquire systemic lupus erythematosus, to chromosomal translocations that result in mixed lineage leukemias, and in the possible spreading of oncogenes and HIV due to horizontal gene transfer.
 ...
PMID:Roles of the major apoptotic nuclease-DNA fragmentation factor-in biology and disease. 1881 Mar 17


1 2 Next >>