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)

Little is known about how a cell's apoptotic threshold is controlled after exposure to chemotherapy, although the p53 tumor suppressor has been implicated. We identified executioner caspase-6 as a transcriptional target of p53. The mechanism involves DNA binding by p53 to the third intron of the caspase-6 gene and transactivation. A p53-dependent increase in procaspase-6 protein level allows for an increase in caspase-6 activity and caspase-6-specific Lamin A cleavage in response to Adriamycin exposure. Specific inhibition of caspase-6 blocks cell death in a manner that correlates with caspase-6 mRNA induction by p53 and enhances long-term survival in response to a p53-mediated apoptotic signal. Caspase-6 is an executioner caspase found directly regulated by p53, and the most downstream component of the death pathway controlled by p53. The induction of caspase-6 expression lowers the cell death threshold in response to apoptotic signals that activate caspase-6. Our results provide a potential mechanism of lowering the death threshold, which could be important for chemosensitization.
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PMID:Apoptotic threshold is lowered by p53 transactivation of caspase-6. 1208 22

The p53 and BRCA1 tumor suppressors are involved in repair processes and may cooperate to transactivate certain genes, including p21WAF/CIP1 and GADD45. We find that the Xeroderma Pigmentosum Complementation group E (XPE) mutated Damaged-DNA binding protein p48 (DDB2) is upregulated by BRCA1 in a p53-dependent manner following UVC, Adriamycin, or Cisplatin exposure. BRCA1 enhances p53 binding to the DDB2 promoter in vivo as well as p53-dependent transactivation of DDB2 promoter-reporter constructs through a classical p53 DNA responsive element. Antisense abrogation of BRCA1 expression abrogates upregulation of DDB2 after UVC or cisplatin exposure. Using a host cell reactivation assay, DNA repair activity is more significantly restored by introduction of BRCA1 into wt as compared to DDB2-deficient cells. Furthermore disappearance of the photoproducts cyclobutane pyrimidine dimer (CPD) and 6-4 photoproduct (6-4PP) was delayed by antisense abrogation of BRCA1 expression in UV-exposed human cells. Thus the DNA repair function of BRCA1 may be attributed in part to p53-dependent transcriptional induction of DDB2. Loss of BRCA1-dependent DDB2 repair function may contribute to cancer susceptibility and cellular sensitivity to DNA damage.
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PMID:BRCA1 transcriptionally regulates damaged DNA binding protein (DDB2) in the DNA repair response following UV-irradiation. 1221 15

Survivin is a member of the inhibitor of apoptosis gene family that is expressed in most human cancers and may facilitate evasion from apoptosis and aberrant mitotic progression. Here, exposure of breast carcinoma MCF-7 or cervical carcinoma HeLa cells to anticancer agents, including Adriamycin, Taxol, or UVB resulted in a 4-5-fold increased survivin expression. Changes in survivin levels after anticancer treatment did not involve modulation of survivin mRNA expression and were independent of de novo gene transcription. Conversely, inhibition of survivin phosphorylation on Thr(34) by the cyclin-dependent kinase inhibitor flavopiridol resulted in loss of survivin expression, and nonphosphorylatable survivin Thr(34)-->Ala exhibited accelerated clearance as compared with wild-type survivin. Sequential ablation of survivin phosphorylation on Thr(34) enhanced tumor cell apoptosis induced by anticancer agents independently of p53 and suppressed tumor growth without toxicity in a breast cancer xenograft model in vivo. These data suggest that Thr(34) phosphorylation critically regulates survivin levels in tumor cells and that sequential ablation of p34(cdc2) kinase activity may remove the survivin viability checkpoint and enhance apoptosis in tumor cells.
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PMID:Suppression of survivin phosphorylation on Thr34 by flavopiridol enhances tumor cell apoptosis. 1251 2

Triptolide (TPL), a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii Hook F, was tested for its antitumor properties in several model systems. In vitro, TPL inhibited the proliferation and colony formation of tumor cells at extremely low concentrations (2-10 ng/ml) and was more potent than Taxol. Likewise, in vivo, treatment of mice with TPL for 2-3 weeks inhibited the growth of xenografts formed by four different tumor cell lines (B16 melanoma, MDA-435 breast cancer, TSU bladder cancer, and MGC80-3 gastric carcinoma), indicating that TPL has a broad spectrum of activity against tumors that contain both wild-type and mutant forms of p53. In addition, TPL inhibited experimental metastasis of B16F10 cells to the lungs and spleens of mice. The antitumor effect of TPL was comparable or superior with that of conventional antitumor drugs, such as Adriamycin, mitomycin, and cisplatin. Importantly, tumor cells that were resistant to Taxol attributable to the overexpression of the multidrug resistant gene 1 were still sensitive to the effects of TPL. Studies on cultured tumor cells revealed that TPL induced apoptosis and reduced the expression of several molecules that regulate the cell cycle. Taken together, these results suggest that TPL has several attractive features as a new antitumor agent.
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PMID:Triptolide inhibits the growth and metastasis of solid tumors. 1253 74

Adriamycin and other DNA-damaging agents have been shown to reduce BRCA2 mRNA levels in breast cancer cell lines, but the mechanism by which this occurs is unknown. In this study, we show that adriamycin and mitomycin C, but not other DNA-damaging agents, repress BRCA2 promoter activity in a dose- and time-dependent manner. We demonstrate that the effect is dependent on wild type p53 and that adriamycin and p53 mediate repression of the BRCA2 promoter by inhibiting binding of an upstream stimulatory factor protein complex to the promoter. In addition, we present evidence indicating that adriamycin and other DNA-damaging agents reduce BRCA2 mRNA and protein levels by altering both BRCA2 mRNA stability and protein stability. Thus, BRCA2 levels in the cell are regulated by three independent mechanisms in a p53-dependent manner.
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PMID:p53 mediates repression of the BRCA2 promoter and down-regulation of BRCA2 mRNA and protein levels in response to DNA damage. 1259 28

Genotoxic stimuli, including anticancer drugs, induce apoptosis in cancer cells through increase of p53, p21WAF1/CIP1, at least in part. Bcl-2 and Bax modify this pathway or directly regulated by p53. Here we studied Adriamycin (ADM)-induced apoptosis in four human bladder cancer cell lines in respect of p53, p21WAF1/CIP1 and Bcl-2 family proteins. After ADM, treatment bladder cancer cells underwent dose-dependent cell death with typical morphologic features of apoptosis. Among four cell lines RT4 with wt p53, low ratio of Bcl-2 to Bax and induction of p21WAF1/CIP1 after ADM treatment, was the most sensitive to induction of apoptosis. Thus, p53, p21WAF1/CIP1, Bcl-2 and Bax status might determine susceptibility of bladder cancer cells to ADM induced apoptosis.
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PMID:Adriamycin (ADM) induced apoptosis in transitional cell cancer (TCC) cell lines accompanied by p21 WAF1/CIP1 induction. 1464 56

Mammalian cells undergo cell cycle arrest in response to DNA damage due to the existence of multiple checkpoint response mechanisms. One such checkpoint pathway operating at the G(1) phase is frequently lost in cancer cells due to mutation of the p53 tumor suppressor gene. However, cancer cells often arrest at the G(2) phase upon DNA damage, due to activation of another checkpoint pathway that prevents the activation Cdc2 kinase. The kinases, Chk1, Wee1, and Myt1 are key regulators of this G(2) checkpoint, which act directly or indirectly to inhibit Cdc2 activity. Here we show that RNA interference (RNAi)-mediated downregulation of Wee1 kinase abrogated an Adriamycin trade mark -induced G(2) checkpoint in human cervical carcinoma Hela cells that are defective in G(1) checkpoint response. Wee1 downregulation sensitized HeLa cells to Adriamycin trade mark -induced apoptosis. Downregulation of Chk1 kinase in Hela cells also caused a significant amount of cell death in dependent of DNA damage. In contrast, Myt1 downregulation also abrogated Adriamycin trade mark -induced G(2) arrest but did not cause substantial apoptosis. Reduction in Wee1, Chk1, or Myt1 levels did not sensitize normal human mammary epithelial cells (HMEC) cells to Adriamycin trade mark -induced apoptosis unlike the situation in Hela cells. Our study reveals distinct roles for Chk1, Wee1, and Myt1 in G(2) checkpoint regulation. The data reported here support the attractiveness of Wee1 and Chk1 is as molecular targets for abrogating the G(2) DNA damage checkpoint arrest, a situation that may selectively sensitize p53-deficient tumor cells to radiation or chemotherapy treatment.
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PMID:Knockdown of Chk1, Wee1 and Myt1 by RNA interference abrogates G2 checkpoint and induces apoptosis. 1500 34

Camptothecin and Adriamycin are clinically important inhibitors for topoisomerase (Topo) I and Topo II, respectively. The ataxia-telangiectasia mutated (ATM) product is essential for ionizing radiation-induced DNA damage responses, but the role of ATM in Topo poisons-induced checkpoints remains unresolved. We found that distinct mechanisms are involved in the activation of different cell cycle checkpoints at different concentrations of Adriamycin and camptothecin. Adriamycin promotes the G(1) checkpoint through activation of the p53-p21(CIP1/WAF1) pathway and decrease of pRb phosphorylation. Phosphorylation of p53(Ser20) after Adriamycin treatment is ATM dependent, but is not required for the full activation of p53. The G(1) checkpoint is dependent on ATM at low doses but not at high doses of Adriamycin. In contrast, the Adriamycin-induced G(2) checkpoint is independent on ATM but sensitive to caffeine. Adriamycin inhibits histone H3(Ser10) phosphorylation through inhibitory phosphorylation of CDC2 at low doses and down-regulation of cyclin B1 at high doses. The camptothecin-induced intra-S checkpoint is partially dependent on ATM, and is associated with inhibitory phosphorylation of cyclin-dependent kinase 2 and reduction of BrdUrd incorporation after mid-S phase. Finally, apoptosis associated with high doses of Adriamycin or camptothecin is not influenced by the absence of ATM. These data indicate that the involvement of ATM following treatment with Topo poisons differs extensively with dosage and for different cell cycle checkpoints.
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PMID:Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms. 1514 Oct 20

Survivin regulates cell division and inhibits apoptosis by blocking caspase activation. The tumor suppressor p53 inhibits cell cycle progression and induces apoptosis. Since Survivin overexpression and loss of wild-type p53 expression/function occur in most cancers, we investigated whether Survivin regulates p53. Stable overexpression of Survivin protects BaF3 cells from Adriamycin-induced apoptosis, while dominant-negative (T34A) and antisense (AS) Survivin accelerate apoptosis. In BaF3 cells and transiently transfected MCF7 breast cancer cells, elevation of total and phospho-Ser15-p53 in response to Adriamycin is blocked by Survivin and enhanced by Survivin disruption. Furthermore, in Adriamycin-treated MCF7 cells, ectopic Survivin decreased p53 mRNA and increased mRNA and protein of the p53 homologues DeltaNp63 and TAp73 and mRNA for DeltaNp73, suggesting that Survivin may differentially regulate p53 family transcription. Concomitant with decreasing p53 mRNA, Survivin decreased Mdm2 mRNA. Survivin disruption by T34A or AS Survivin resulted in reduced Mdm2 protein. The caspase inhibitor, Z-VAD-FMK, blocked the decrease in Mdm2 as well as the increase in p53 resulting from Survivin disruption, indicating that Survivin regulates Mdm2 at the post-translational level. Proteosome inhibition confirmed that reduced p53 protein observed in cells overexpressing Survivin is due to enhanced p53 degradation resulting from Survivin-mediated inhibition of Mdm2 cleavage by caspases. In summary, our results identify regulatory interactions between Survivin and p53 at the mRNA and protein levels, and suggest that the p53 homologues DeltaNp63, TAp73 and DeltaNp73 may also be regulated by Survivin.
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PMID:Survivin regulates the p53 tumor suppressor gene family. 1536 31

The overexpression of the inhibitor of apoptosis protein, survivin, may provide tumor cells with a distinct survival advantage in situ; hence, therapeutic strategies have been designed to inhibit its expression. In this study, we ectopically expressed the interferon regulatory factor (IRF)-1 protein in the breast carcinoma cell lines MDA-MB-468 and SK-BR-3 using a recombinant adenovirus (Ad-IRF-1). By screening microarray analysis of cDNA from the human breast cancer cell line MDA-MB-468 infected with Ad-IRF-1, we observed a 15-fold down-regulation of the survivin gene when compared with uninfected cells. Consequently, we tested survivin expression in Ad-IRF-1-infected MDA-MB-468 and SK-BR-3 breast cancer cell lines. Immunoblotting analyses supported the contention that ectopic expression of the IRF-1 protein results in down-regulation of survivin protein expression that is independent of p53. In addition, Ad-IRF-1 infection of these human breast cancer cell lines induces the expression of p21. We also report that increased apoptosis is observed in tumor cells infected with Ad-IRF-1 compared with Ad-Psi5 mock-infected cells and that cell death is further augmented when the IRF-1-infected cells are cultured with Adriamycin. Moreover, in a xenogeneic mouse model of breast carcinoma, in vivo treatment of tumor-bearing mice with intratumoral Ad-IRF-1 injections results in tumor growth inhibition. In resected tumors from mice that had been treated with Ad-IRF-1, tumor cells that express the IRF-1 transgene have a predominant IRF-1-positive, survivin-negative phenotype. Collectively, these observations suggest that therapies designed to enhance IRF-1 expression within tumor cells may represent novel treatment strategies for breast cancer.
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PMID:Ectopic expression of interferon regulatory factor-1 promotes human breast cancer cell death and results in reduced expression of survivin. 1554 8


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