Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, several tumor necrosis factor receptor 1 (TNF-R1) and Fas-related death receptors have been discovered and include DR3, DR4, DR5 and DR6. These receptors contain an extracellular region containing varying numbers of cysteine-rich domains and an intracellular region that contains the death domain. The death receptors are activated in a ligand-dependent or independent manner and transduce apoptotic signals via their respective intracellular death domains. In addition to death receptors, several decoy molecules have also been identified and include DcR1/TRID, DcR2/TRUNDD, DcR3 and osteoprotegrin (OPG). The decoy molecules do not transduce apoptotic signals but rather compete with the death receptors for ligand binding and thereby inhibit ligand-induced apoptosis. Recent evidence suggests that p53 upregulates the expression of death receptors Fas and DR5, and thus, may mediate apoptosis in part via Fas and/or DR5. However, p53 also regulates the expression of TRAIL decoy receptors DcR1/TRID and DR2/TRUNDD. Although the significance of p53-dependent regulation of decoy receptors remains unclear, evidence suggests that DcR1/TRUNDD appears to inhibit 53-mediated apoptosis. It is, therefore, possible that p53 may blunt its DR5-dependent apoptotic effects by controlling the levels of decoy receptors.
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PMID:Death and decoy receptors and p53-mediated apoptosis. 1094 51

Due to its critical involvement in cell cycle control and apoptotic signaling, the transcription factor p53 has become the most important tumor suppressor currently under investigation. TP53 is the most frequently mutated gene in human cancers and is thought to play a crucial role in malignant transformation. Therefore, p53 appears to be an appealing target for gene therapy. Adenoviral-based p53 gene transfection is now being introduced in large clinical trials. Viral cell entry was found to be the rate-limiting step of gene delivery and thus of therapeutic efficiency. Attachment of adenoviruses to the target cell surface is mediated through the coxsackie-adenovirus receptor, and internalization is achieved via interactions with integrins of the alpha v beta(3) and alpha v beta(5) class. The assumption that the restitution of the p53-dependent apoptotic pathway results in a higher responsiveness of solid tumors to cytostatic agents remains a major matter of debate. Combinations of p53-based gene therapy with other components involved in apoptosis, such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/APO2L, or agents neutralizing tumor-promoting antiapoptotic signals, such as humanized anti-growth factor antibodies, should further improve the effectiveness of cancer treatment in the future.
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PMID:New insights into p53 regulation and gene therapy for cancer. 1100 53

Most chemotherapeutic drugs can induce tumor cell death by apoptosis. Analysis of the molecular mechanisms that regulate apoptosis has indicated that anticancer agents simultaneously activate several pathways that either positively or negatively regulate the death process. The main pathway from specific damage induced by the drug to apoptosis involves activation of caspases in the cytosol by pro-apoptotic molecules such as cytochrome c released from the mitochondrial intermembrane space. At least in some cell types, anticancer drugs also upregulate the expression of death receptors and sensitize tumor cells to their cognate ligands. The Fas-mediated pathway could contribute to the early steps of drug-induced apoptosis while sensitization to the cytokine TRAIL could be used to amplify the response to cytotoxic drugs. The Bcl-2 family of proteins, that includes anti- and pro-apoptotic molecules, regulates cell sensitivity mainly at the mitochondrial level. Anticancer drugs modulate their expression (eg through p53-dependent gene transcription), their activity (eg by phosphorylating Bcl-2) and their subcellular localization (eg by inducing the translocation of specific BH3-only pro-apoptotic proteins). Very early after interacting with tumor cells, anticancer drugs also activate lipid-dependent signaling pathways that either increase or decrease cell ability to die by apoptosis. In addition, cytotoxic agents can activate protective pathways that involve activation of NFkappaB transcription factor, accumulation of heat shock proteins such as Hsp27 and activation of proteins involved in cell cycle regulation. This review discusses how modulation of the balance between noxious and protective signals that regulate drug-induced apoptosis could be used to improve the efficacy of current therapeutic regimens in hematological malignancies.
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PMID:Positive and negative regulation of apoptotic pathways by cytotoxic agents in hematological malignancies. 1102 59

Ionizing radiation is a major tool for cancer treatment. The response of eukaryotic cells to ionizing radiation includes apoptosis, a process which requires activation of multiple genes. We sought to determine whether radiation-induced gene expression plays a role in radiation-induced apoptosis. We found Apo2 ligand (Apo2L, also called TRAIL) mRNA induction following gamma-irradiation of Jurkat, MOLT-4, CEM, and PBMC, all human T lineage-derived cells. Increased Apo2L protein levels were found in MOLT-4 and Jurkat cells. Radiation also activated the Apo2L death receptor (DR)5 (also called Apo2, TRAIL-R2, or KILLER) in MOLT-4 cells, which harbor a wild-type p53. We isolated 1152 bp of 5' flanking region of the Apo2L gene and a shorter fragment of 716 bp, both of which showed promoter activity driving the expression of a luciferase reporter gene; however, the response to radiation in MOLT-4 cells was lost when only 430 bp of 5' proximal flanking sequence was maintained. Exogenous Apo2L induced phosphatidylserine exposure on cell membranes, caspase 8 and caspase 3 activation, key markers of apoptosis, confirming that the Apo2L/DR5 pathway is functional in these cells. Bid, a Bcl-2 family protein also known to contribute to receptor-mediated apoptosis, was also activated. To determine whether Apo2L and DR5 were critical for radiation signaling to apoptosis, we stably expressed a dominant negative DR5delta-receptor in Jurkat cells. Cell survival was significantly augmented, indicating that increased Apo2L expression contributed to radiation-induced apoptosis. Clonogenic assays demonstrated that purified, recombinant soluble Apo2L enhanced the lethality of low, therapeutic doses (1-2 Gy) of gamma-irradiation. These data suggest that production of Apo2L may cooperate synergistically with the cytotoxic effect of radiation, and that combinations of Apo2L and radiation may become a powerful tool in clinical therapy.
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PMID:Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor 5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells. 1105 70

In present studies, treatment with tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL, also known as Apo-2 ligand [Apo-2L]) is shown to induce apoptosis of the human acute leukemia HL-60, U937, and Jurkat cells in a dose-dependent manner, with the maximum effect seen following treatment of Jurkat cells with 0.25 microg/mL of Apo-2L (95.0% +/- 3.5% of apoptotic cells). Susceptibility of these acute leukemia cell types, which are known to lack p53(wt) function, did not appear to correlate with the levels of the apoptosis-signaling death receptors (DRs) of Apo-2L, ie, DR4 and DR5; decoy receptors (DcR1 and 2); FLAME-1 (cFLIP); or proteins in the inhibitors of apoptosis proteins (IAP) family. Apo-2L-induced apoptosis was associated with the processing of caspase-8, Bid, and the cytosolic accumulation of cytochrome c as well as the processing of caspase-9 and caspase-3. Apo-2L-induced apoptosis was significantly inhibited in HL-60 cells that overexpressed Bcl-2 or Bcl-x(L). Cotreatment with either a caspase-8 or a caspase-9 inhibitor suppressed Apo-2L-induced apoptosis. Treatment of human leukemic cells with etoposide, Ara-C, or doxorubicin increased DR5 but not DR4, Fas, DcR1, DcR2, Fas ligand, or Apo-2L levels. Importantly, sequential treatment of HL-60 cells with etoposide, Ara-C, or doxorubicin followed by Apo-2L induced significantly more apoptosis than treatment with Apo-2L, etoposide, doxorubicin, or Ara-C alone, or cotreatment with Apo-2L and the antileukemic drugs, or treatment with the reverse sequence of Apo-2L followed by one of the antileukemic drugs. These findings indicate that treatment with etoposide, Ara-C, or doxorubicin up-regulates DR5 levels in a p53-independent manner and sensitizes human acute leukemia cells to Apo-2L-induced apoptosis. (Blood. 2000;96:3900-3906)
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PMID:Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells. 1109 76

KILLER/DR5 is a death-domain-containing proapoptotic receptor that binds to the cytotoxic ligand TRAIL. It was originally reported that induction of KILLER/DR5 mRNA following DNA damage was p53-dependent, but some drugs that induce apoptosis can upregulate KILLER/DR5 mRNA expression in cell lines with mutated p53. We further extend those findings by classifying the capability of various apoptosis-inducing drugs to increase the expression of KILLER/DR5 mRNA in a p53-independent manner. beta-Lapachone, a topoisomerase inhibitor, increased KILLER/DR5 mRNA in colon cancer cell lines with wild-type p53 but not with mutant p53. In contrast, betulinic acid, a novel chemotherapeutic compound, induced apoptosis and KILLER/DR5 mRNA in melanoma and glioblastoma cells through a p53-independent mechanism. The synthetic glucocorticoid dexamethasone elevated KILLER/DR5 mRNA in glioblastoma, ovarian cancer, and colon cancer cell lines with mutant p53 undergoing apoptosis, and this induction was inhibited by the transcriptional inhibitor actinomycin D. Although another glucocorticoid, prednisolone, also induced apoptosis, it did not increase KILLER/DR5 mRNA. Finally, the cytokine interferon-gamma (IFN-gamma) induced apoptosis and KILLER/DR5 in cell lines with mutant p53, and the induction of KILLER/DR5 mRNA by IFN-gamma was delayed in cells lacking wild-type STAT1, a transcription factor implicated in IFN-gamma signaling. Similarly, the induction of KILLER/DR5 mRNA by the cytokine TNF-alpha was also delayed in cell lines with mutated STAT1. These findings suggest that KILLER/DR5 may play a role in p53-independent apoptosis induced by specific drugs and warrants further investigation as a novel target for chemotherapy of tumors lacking wild-type p53.
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PMID:p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. 1113 40

The cytotoxic ligand TRAIL is a promising anti-cancer agent that is entering into clinical trials. We previously identified a major subgroup of TRAIL resistant cancer cell lines with absent, or reduced DR4 expression containing a K441R polymorphism or harboring elevated levels of the caspase activation inhibitor FLIP. In the present study, we explored the use of a gene therapeutic approach utilizing p53, delivered by an adenovirus-p53 (Ad-p53) vector, which directly controls expression of the TRAIL receptor KILLER/DR5 in a panel of 8 cell lines including normal and TRAIL sensitive or resistant cancers. The functional status of the delivered p53 was monitored by detection of induced p21WAF1 expression by immunocytochemistry. In normal cells, which are TRAIL resistant, TRAIL did not reduce cell viability over and above the effect of Ad-p53 alone. All cancer cell lines were sensitive to Ad-p53 and up-regulated expression of the TRAIL receptor KILLER/DR5. TRAIL-resistant cancer cells became more sensitive to TRAIL at low Ad-p53 multiplicities of infection but TRAIL resistance was not completely overcome in one TRAIL-resistant cell line probably because of a high level of expression of FLIP. The results reveal that Ad-p53 induces the TRAIL receptor KILLER/DR5 and, like radiation or chemotherapy may effectively reverse TRAIL resistance.
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PMID:Enhanced TRAIL sensitivity by p53 overexpression in human cancer but not normal cell lines. 1117 88

The heme oxygenase (HO) isozymes catalyze oxidation of the heme molecule to biliverdin and carbon monoxide (CO) with the release of chelated iron. Presently, we have defined, for the first time, propensity for site of injury-directed induction of isozymes--the stress-inducible isozyme, HO-1, responds distal (below) and the glucocorticoid (GC)-inducible HO-2 responds proximal (above) to the site of injury. We have also shown that reactive iron (Fe3+) and cGMP staining spatially resemble that of HO-1; which, in turn, colocalizes in motor neurons with transcription factors: Fas-associated protein containing death domain (FADD), tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p53. Spinal cord injury (SCI) was inflicted by clip compression for 30 min, and analyses were carried out after 4 h or 16 h. When compared with spinal cord segments proximal to the site of injury, northern blot analysis showed remarkably higher levels of HO-1 mRNA distal (below) to the site of injury at both time points. In contrast, HO-2 mRNA levels were elevated proximal (above) to the site of injury and more prominently at 16 h post SCI. Immunohistochemical analyses were carried out using 2 x 5 mm segments above and below the compression site. When compared with segments above the site of injury, the intensity of HO-1 immunostaining and the number of HO-1 positive neurons in the ventral horn motor neurons were prominently increased in segments below the injury. Western blot analysis confirmed the observations. HO-2 protein was mapped to the ventral horn motor neurons, oligodendrocytes, the Clarke's nucleus neurons and the ependymal cells. When compared with segments below the site of injury, neuronal HO-2 staining intensity was increased above the site of injury, and most notably at 16 h. These observations were also confirmed by western blotting and HO activity measurements. Tissue Fe3+ and cGMP staining were increased and prominently mapped below the site of injury, where cGMP colocalized with HO-1 in the nucleus of the motor neurons. Also, a site of injury-directed pattern of induction of FADD, TRAIL, and p53 immunoreactivity, and a widespread colocalization of the oncogenes with HO-1 protein, were found within motor neurons below the level of injury. We forward the hypothesis that HO-1 and HO-2 have different roles in the defense mechanisms of the injured nervous system. We hypothesize that HO-1 protects against further damage by contributing to controlled cell death through their intrinsic suicide program, while HO-2 is involved in suppression of inflammatory response by NO derived radicals.
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PMID:Site of injury-directed induction of heme oxygenase-1 and -2 in experimental spinal cord injury: differential functions in neuronal defense mechanisms? 1120 17

Apoptosis is an intrinsic and fundamental biologic process that plays a critical role in the normal development of multicellular organisms and in the maintainance of tissue homeostasis. Some of the well known regulators of apoptosis are cytokines of the tumor necrosis factor (TNF) ligand family, such as Fas ligand (Fas L) and TNF, which induce apoptosis by activation of their corresponding receptors, Fas and TNFR-1. Recently, a new member of the TNF family known as TRAIL (TNF-related apoptosis-inducing ligand) was identified and shown to induce p53-independent apoptosis in a variety of tumor cell lines but not in normal cells. Four human receptors for TRAIL were also recently identified and designated TRAIL-R1, -R2, -R3, and -R4. The aim of this study is to examine whether TRAIL and TRAIL receptors (-R1, -R2, -R3) are expressed in uterine cervical cancer and whether it is correlated with apoptosis, TRAIL, and TRAIL receptors. The subjects were 20 patients who were diagnosed with cervical cancer. Western blotting was performed in nine cases and immunohistochemical staining for TRAIL and TRAIL receptors (-R1, -R2, -R3) and TUNEL method for detection of apoptosis was performed in 11 cases. There were proteins for TRAIL, TRAIL-R1, -R2, and -R3 in tissues from cervical cancer. All TRAIL receptors were expressed in both normal cervical epithelium and tumor cells, and TRAIL-R1 and -R2 were more strongly expressed in tumor cells than normal epithelium (P < 0.05). Apoptosis correlated with expression of TRAIL-R1 and -R2 (P < 0.05). This study suggests that TRAIL induces apoptosis in cervical cancer through its receptors.
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PMID:Expression of TRAIL (TNF-related apoptosis-inducing ligand) receptors in cervical cancer. 1124 Jul 8

Chronic obstructive uropathy (COU) created by unilateral ureteric ligation is associated with increased renal cell apoptosis and p53 expression. Genetically engineered mice were used to examine the role of p53 in renal cell apoptosis in COU and the involved molecular pathways. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice were examined at days 4, 7, 15, 20, and 30 for apoptosis, and mRNA were examined for p53, members of the bcl-2 family, the death receptor family, and the common effectors of apoptosis. Obstructed kidneys in p53+/- and p53-/- mice exhibited equal attenuation of tubular and interstitial cell apoptosis (70 and 50%, respectively), compared with p53+/+ mice. However, p53 gene deficiency did not confer complete protection from apoptosis. Obstructed kidneys from p53-/- mice did not express p53 mRNA, whereas those from p53+/- and p53+/+ mice displayed mild and marked increase in their expression, respectively. Obstructed kidneys in p53+/+, p53+/-, and p53-/- mice displayed upregulation of mRNA for members of the bcl-2 family and most of the death receptor family, except for a lower level of tumor necrosis factor receptor-1, TRAIL, and FAP in p53+/+ mice. Obstructed kidneys in p53-/- and p53+/- mice showed virtual absence of caspase 11 and marked attenuation of caspases 1 and 12, contrasted with their strong expression in p53+/+ kidneys. These data suggest that apoptosis in obstructed kidneys involves p53-dependent as well as p53-independent pathways. The p53-dependent pathway may involve activation of caspases 1, 11, and 12, whereas the p53-independent pathway may involve activation of members of the bcl-2 and death receptor families.
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PMID:Role of p53-dependent activation of caspases in chronic obstructive uropathy: evidence from p53 null mutant mice. 1131 57


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