Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor E2F1 does not only induce cell proliferation but also shows the strongest proapoptotic effect of all E2F family members as part of an antitumor safeguard mechanism. We have recently identified KIAA0767 as a novel p53-independent target of E2F1. Here, we investigated the biological function of interaction. Overexpression studies of KIAA0767, termed D(eath)-I(nducing)-P(rotein), revealed its strong proapoptotic effect. DIP greatly reduced cell viability in several in vitro systems accompanied by typical apoptotic features such as caspase-3 activation and cleavage of poly(ADP-ribose)-polymerase. Endogenous DIP levels increased following E2F1 activation. Yet, inhibition of endogenous DIP function by small interfering RNA rescued p53-negative cells from E2F1-induced apoptosis, indicating that DIP is an essential mediator of the p53-independent E2F1 death pathway. Localization studies showed that DIP localizes to the mitochondria, where endogenous DIP is upregulated following E2F1 induction. These results provide new insights to the incompletely understood regulatory mechanisms of E2F1-induced apoptosis.
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PMID:A novel mitochondrial protein DIP mediates E2F1-induced apoptosis independently of p53. 1556 77

Previous studies have shown that proteins extracted from Zebrafish embryo share some cytostatic characteristics in cancer cells. Our study was conducted to ascertain the biological properties of this protein network. Cancer cell growth and apoptosis were studied in Caco2 cells treated with embryonic extracts. Cell proliferation was significantly inhibited in a dose-dependent manner. Cell-cycle analysis in treated cells revealed a marked accumulation in the G(2)/M phase preceding induction of apoptosis. Embryo proteins induced a significant reduction in FLIP levels, and increased caspase-3 and caspase-8 activity as well as the apoptotic rate. Increased phosphorylated pRb values were obtained in treated Caco2 cells: the modified balance in pRb phosphorylation was associated with an increase in E2F1 values and c-Myc over-expression. Our data support previous reports of an apoptotic enhancing effect displayed by embryo extracts, mainly through the pRb/E2F1 apoptotic pathway, which thus suggests that Zebrafish embryo proteins have complex anti-cancer properties.
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PMID:Zebrafish embryo proteins induce apoptosis in human colon cancer cells (Caco2). 1682 Sep 66

Monoamine oxidase A (MAO A) degrades serotonin, norepinephrine, and dopamine and produces reactive oxygen that may cause neuronal cell death. We have previously reported that a novel transcription factor R1 (RAM2/CDCA7L/JPO2) inhibits the MAO A promoter and enzymatic activities. This study reports the roles of MAO A and R1 in apoptosis and proliferation. We have found that in serum starvation-induced apoptosis, p38 kinase, MAO A, and caspase-3 were increased, whereas Bcl-2 and R1 were reduced. Using a p38 kinase inhibitor, R1 overexpression, and MAO A inhibitor, we have shown that MAO A and R1 are downstream of p38 kinase and Bcl-2, but upstream of caspase-3. Inhibition of MAO A prevents cell apoptosis. This notion was further supported by the finding that serum starvation-induced apoptosis is reduced in cortical brain cells from MAO A-deficient mice compared with WT. In addition, we found that MAO A and R1 are involved in the c-Myc-induced proliferative signaling pathway in the presence of serum. Immunoprecipitation and immunohistochemistry experiments indicate that the oncogene c-Myc colocalizes with R1 and induces R1 gene expression. Using R1 overexpression, R1 small interfering RNA, and a MAO A inhibitor, we found that R1 and MAO A act upstream of cyclin D1 and E2F1. In summary, this study demonstrates the functions of MAO A and its repressor R1 in apoptotic signaling pathways.
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PMID:Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. 1682 76

Mildly affected individuals from xeroderma pigmentosum complementation group G (XP-G) possess single amino acid substitutions in the XPG protein that adversely affects its 3' endonuclease function in nucleotide excision repair. More serious mutations in the XPG gene generate truncated or unstable XPG proteins and result in a particularly early and severe form of the combined XP/CS complex. Following UV irradiation, cells from such XP-G/CS patients enter apoptosis more readily than other DNA repair-deficient cells. Here, we explore the mechanisms by which UV triggers the apoptotic cell death program in XP-G and XP-G/CS primary fibroblasts. Activation of the CD95 signalling pathway occurs within minutes and it is the earliest detectable post-UV event in such cells. This is rapidly followed by activation of caspase-8 then caspase-3. Several hours later caspase-9 becomes activated and the mitochondrial membrane potential drops, but without any obvious prior release of cytochrome c. Although p53 accumulates in XPG-deficient cells after UV irradiation, use of RNA interference demonstrates that p53 is not required for their UV-induced apoptotic response. p53 ablation of wild-type fibroblasts reduces MDM2 mRNA levels, inhibits accumulation of the 90kDa/92kDa Mdm2 isoforms, and prevents the nuclear relocalisation of Mdm2 after UV treatment. The same post-UV effects occur in XPG-deficient cells that express normal p53 levels. These results emphasise the importance of the extrinsic apoptotic pathway and aberrant Mdm2 events for the severe UV-induced apoptosis of XPG-deficient primary fibroblasts. XP-G/CS cells constitutively overexpress the pro-apoptotic Bax protein and a long isoform of the E2F1 transcription factor that controls S phase entry, which may prime them to enter apoptosis very readily after UV irradiation.
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PMID:UV-induced apoptosis in XPG-deficient fibroblasts involves activation of CD95 and caspases but not p53. 1720 56

TRIP-Br1 and TRIP-Br2 are potent cell growth promoting factors that function as components of the E2F1/DP1 transcription complex to integrate positive growth signals provided by PHD zinc finger- and/or bromodomain-containing transcription factors. TRIP-Br1 has been demonstrated to be an oncogene. We recently reported that antagonism of the TRIP-Br integrator function by synthetic decoy peptides that compete with TRIP-Br for binding to PHD zinc finger- and/or bromodomain-containing proteins elicit an anti-proliferative effect and induces caspase-3-independent sub-diploidization in cancer cells in vitro. We now demonstrate the chemotherapeutic potential of TRIP-Br decoy peptides for the treatment of cutaneous and intracavitary lesions in vitro as well as in vivo in representative human nasopharyngeal cancer (CNE2), cervical cancer (Ca Ski) and melanoma (MeWo) cancer cell lines. In vitro, BrdU incorporation, colony formation assays and cell cycle analysis confirmed that TRIP-Br decoy peptides possess strong anti-proliferative effects and induce nuclear sub-diploidization in cancer cells. In vivo, CNE2, Ca Ski and MeWo-derived chick embryo chorioallantoic membrane (CAM) tumor xenografts were used to evaluate the effect of topically applied TRIP-Br peptides. Confocal microscopy and flow cytometric analysis demonstrated that cells comprising the tumor xenografts efficiently internalized topically applied FITC-labeled peptides. Fifty muM of TRIP-Br1 decoy peptide significantly suppressed the growth of NPC2-derived human nasopharyngeal tumors, while 50 muM of TRIP-Br2 decoy peptide significantly inhibited tumor growth in all three CAM tumor xenograft models. Two hundred muM of TRIP-Br1 decoy peptide significantly inhibited MeWo-derived tumors. These results suggest that the TRIP-Br integrator function may represent a novel chemotherapeutic target for the treatment of human cutaneous and intracavitary proliferative lesions.
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PMID:Exploiting the TRIP-Br family of cell cycle regulatory proteins as chemotherapeutic drug targets in human cancer. 1750 96

Nucleophosmin/B23 is a major multifunctional nucleolar phosphoprotein that plays a critical role in ribosome biogenesis and cell proliferation. Arf tumor suppressor binds B23 and enhances its sumoylation. However, the biological effects of this event remain unknown. Here we show that B23 is sumoylated on both Lysine 230 and 263 residues, but the latter is the major one. Mutation of K263, but not K230, into R abolishes its centrosomal and nucleolar residency. Moreover, Rb binds to wild-type B23, but fails to interact with K263R. Sumoylation enhances B23 binding to Rb. Consequently, B23 potently stimulates E2F1-mediated transcriptional activity, which is abolished in B23 K263R. Further, K263R mutation makes B23 vulnerable to caspase-3 cleavage and sensitizes cells to apoptosis. Surprisingly, K230R mutant strongly binds to phosphatidylinositol-3,4,5-trisphosphate and suppresses DNA fragmentation. Thus, B23 sumoylation regulates its subcellular localization, cell proliferation, and survival activities.
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PMID:Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival. 1753 15

The molecular genetic events underlying thyroid carcinogenesis are not well understood. Mice harboring a dominant-negative mutant thyroid hormone receptor-beta (TRbeta(PV/PV) mice) spontaneously develop follicular thyroid carcinoma similar to human cancer. The present study aimed to elucidate the role of the steroid receptor coactivator-3 (SRC-3) in thyroid carcinogenesis in vivo by using the offspring from the cross of TRbeta(PV/PV) and SRC-3(-/-) mice. TRbeta(PV/PV) mice deficient in SRC-3 (TRbeta(PV/PV)SRC-3(-/-) mice) had significantly increased survival, decreased thyroid tumor growth, delayed tumor progression and lower incidence of distant metastasis as compared with TRbeta(PV/PV) mice with SRC-3 (TRbeta(PV/PV)SRC-3(+/+) mice). Further, in vivo and in vitro analyses of multiple signaling pathways indicated that SRC-3 deficiency could lead to (1) inhibition of cell cycle progression at the G(1)/S transition via controlling the expression of cell cycle regulators, such as E2F1; (2) induction of apoptosis by controlling the expression of the Bcl-2 and caspase-3 genes and (3) suppression of neovascularization and metastasis, at least in part, through modulating the vascular endothelial growth factor gene expression. Taken together, SRC-3 could play important roles through regulating multiple target genes and signaling pathways during thyroid carcinogenesis, understanding of which should direct future therapeutic options for thyroid cancer.
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PMID:The steroid receptor coactivator-3 is a tumor promoter in a mouse model of thyroid cancer. 1765 82

Alzheimer's disease (AD) is the major cause of dementia, accounting for 50% to 70% of the late-onset patients, with 17 to 20 million affected. It is characterized by neurofibrillary tangles, neuronal loss, and amyloid plaques in tissues of the cortex, hippocampus, and amygdala. Apoptosis or programmed cell death appears in the progression of AD. In this study, we investigated the gene expression of 14 apoptotic genes (E2F1, p21/WAF, ICE-LAP3, Fas Antigen, CPP-32, GADD153, ICE-beta, c-Fos, c-Jun, Bax-alpha, Bcl-2, Bcl-(x)L, BAK, and p53) in 5 normal and 6 AD human hippocampal tissues, using reverse transcription-polymerase chain reaction. Our results show an upregulation of gene expression in AD patients for c-Fos and BAK. ICE-beta, c-Jun, Bax-alpha, Bcl-x(L), p53, and GADD153 were found to be upregulated in some AD samples but were not detected or downregulated in other AD or normal samples. No gene expression was found for E2F1 , p21/WAF, ICE-LAP3, Fas Antigen, CPP32, or Bcl-2. These results indicate significant increases in c-Fos , c-Jun, and Bak; therefore, we suggest that these genes may be critical in the apoptotic cascades of AD.
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PMID:Apoptotic gene expression in Alzheimer's disease hippocampal tissue. 1771 63

Cerebellar granule neurons (CGNs) undergo apoptosis when deprived of depolarizing concentration of potassium. A key regulator of cell cycle, E2F1, was believed to play a role in CGN apoptosis induced by potassium deprivation. However, here we demonstrated that although E2F1 was upregulated in wild type CGNs following potassium deprivation, CGNs that derived from E2F1 knockout mice underwent apoptosis at a similar rate as the wild type. Analysis of the apoptotic neurons revealed no difference in the activation of caspase-3 in E2F1 null and wild type CGNs. Furthermore, knockdown of E2F1 expression by RNA interference failed to attenuate the apoptosis of CGNs induced by potassium deprivation. Taken together, our results suggested that E2F1 is not essential for apoptosis induced by potassium deprivation in CGNs.
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PMID:E2F1 is not essential for apoptosis induced by potassium deprivation in cerebellar granule neurons. 1772 64

We recently isolated 20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol (25-OCH3-PPD), a natural product from Panax notoginseng, and demonstrated its cytotoxicity against a variety of cancer cells. Here we report the effects of this compound in vitro and in vivo on human prostate cancer cells, LNCaP (androgen-dependent) and PC3 (androgen-independent), in comparison with three structurally related ginsenosides, ginsenoside Rh2, ginsenoside Rg3, and 20(S)-protopanaxadiol. Of the four test compounds, 25-OCH3-PPD was most potent. It decreased survival, inhibited proliferation, induced apoptosis, and led to G1 cell cycle arrest in both cell lines. It also decreased the levels of proteins associated with cell proliferation (MDM2, E2F1, cyclin D1, and cdks 2 and 4) and increased or activated pro-apoptotic proteins (cleaved PARP, cleaved caspase-3, -8, and -9). In LNCaP cells, 25-OCH3-PPD inhibited the expression of the androgen receptor and prostate-specific antigen. Moreover, 25-OCH3-PPD inhibited the growth of prostate cancer xenograft tumours. Combining 25-OCH3-PPD with conventional chemotherapeutic agents or with radiation led to potent antitumour effects; tumour regression was almost complete following administration of 25-OCH3-PPD and either taxotere or gemcitabine. 25-OCH3-PPD also demonstrated low toxicity to noncancer cells and no observable toxicity in animals. In conclusion, our preclinical data indicate that 25-OCH3-PPD is a potential therapeutic agent against both androgen-dependent and androgen-independent prostate cancer.
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PMID:20(S)-25-methoxyl-dammarane-3beta, 12beta, 20-triol, a novel natural product for prostate cancer therapy: activity in vitro and in vivo and mechanisms of action. 1825 23


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