Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chromatin restricts the accessibility of DNA to regulatory factors; its remodeling over the regulatory regions contributes to the control of gene expression. An increasing number of evidence links defects in chromatin remodeling machinery and cancer. Our aim is to elucidate the role of chromatin structure in the control of the expression of hormone-induced genes in breast cell lines estrogen-dependent or -independent for growth. Mammary tumor growth is controlled by steroid hormones via their nuclear receptor and by growth factors via tyrosine kinase receptors. 50 % of these tumors elude to hormonal control. This limits the anti-estrogen therapy. As a model, we have analyzed in several cell lines the chromatin organization of the regulatory regions of two genes, pS2 that is associated with a good prognostic, and cathepsin D (catD) that is a bad prognostic marker. The expression of the two genes is estrogen-regulated in estrogen-dependent cell line MCF7. In contrast in the hormone-independent cell line MDA MB 231, pS2 is not expressed and catD is constitutively expressed. Within the regulatory regions of pS2 gene, we have localized two regions that undergo a hormone-dependent change in chromatin structure in MCF7 cells but not in MDA MB 231. The lack of chromatin remodeling in MDA MB 231 cells is not due to the absence of expression of the estrogen receptor in the cell line. The expression of pS2 gene can be correlated with chromatin remodeling over the regulatory regions of pS2 gene. In contrast catD regulatory regions did not display hormone-dependent changes in chromatin structure, suggesting that hormone regulation takes place within regions with a constitutively open chromatin structure.
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PMID:[Chromatin remodeling in estrogen-dependent and independent human breast cancer cell lines]. 1089 64

Chromatin restricts the accessibility of DNA to regulatory factors; its remodelling over the regulatory regions contributes to the control of gene expression. An increasing number of evidence links defects in chromatin remodelling machinery and cancer. Our aim is to elucidate the role of chromatin structure in the control of the expression of hormone-induced genes in breast cell lines oestrogen-dependent or -independent for growth. Mammary tumour growth is controlled by steroid hormones via their nuclear receptor and by growth factors via tyrosine kinase receptors. 50% of these tumours elude to hormonal control. This limits the anti-oestrogen therapy. As a model, we have analysed in several cell lines the chromatin organisation of the regulatory regions of two genes, pS2 that is associated with a good prognostic, and cathepsin D (catD) that is a bad prognostic marker. The expression of the two genes is oestrogen-regulated in oestrogen-dependent cell line MCF7. In contrast in the hormone-independent cell line MDA MB 231, pS2 is not expressed and catD is constitutively expressed. Within the regulatory regions of pS2 gene, we have localised two regions that undergo a hormone-dependent change in chromatin structure in MCF7 cells but not in MDA MB 231 and that can be correlated with gene expression. In contrast catD regulatory regions did not display hormone-dependent changes in chromatin structure, suggesting that hormone regulation takes place within regions with a constitutively open chromatin structure.
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PMID:Chromatin remodeling in hormone-dependent and -independent breast cancer cell lines. 1095 22

Estrogen receptor-alpha (ER alpha) is a ligand-activated transcription factor and a member of the nuclear receptor superfamily. The classic mechanism of ER alpha action is associated with estrogen-induced formation of a nuclear ER alpha homodimer, binding to 5'-regulatory estrogen response elements (EREs) in target gene promoters, interaction with other nuclear proteins, and general transcription factors to activate gene expression. ER alpha also interacts with Sp1 protein to transactivate genes through binding Sp1(N)xERE or Sp1(N)xERE half-site (1/2) motifs where both ER alpha and Sp1 bind DNA elements. Activation through Sp1(N)xERE1/2 requires interactions of both proteins with their cognate DNA elements as well as additional nuclear factors to form a functional ER alpha/Sp1-DNA complex. Recent studies also show that ER alpha and Sp1 physically interact and ER alpha preferentially binds to the C-terminal DNA-binding domain of Sp1 protein. Moreover, ER alpha/Sp1 can activate transcription from a consensus GC-rich Sp1 binding site in transient transfection studies in MCF-7 human breast cancer cells, and this response is also observed with ER alpha variants that do not contain the DNA-binding domain. Several genes that are induced by estrogens in MCF-7 cells are activated through one or more GC-rich sites in their regulatory regions and these include the cathepsin D, E2F1, bcl-2, c-fos, adenosine deaminase, insulinlike growth factor binding protein 4, and retinoic acid receptor alpha 1 genes. ER alpha/Sp1 and ER beta/Sp1 action is dependent on ligand structure and cell context and ER beta/Sp1 is primarily associated with decreased ligand-dependent gene expression. ER alpha/Sp1, like ER alpha/AP1, represents a pathway for hormone activation of genes in which the receptor does not bind DNA, and results of ongoing studies suggest that ER alpha/Sp1 plays an important role in transcriptional activation of multiple growth regulatory genes in breast cancer cells.
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PMID:Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. 1134

The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphtalene carboxylic acid (AHPN/CD437) has been proven to be a potent inducer of apoptosis in a variety of tumor cell types. However, the mechanism of its action remains to be elucidated. Recent studies suggest that the lysosomal protease cathepsin D, when released from lysosomes to the cytosol, can initiate apoptosis. In this study, we examined whether cathepsin D and free radicals are involved in the CD437-induced apoptosis. Exposure of human leukemia HL-60 cells to CD437 resulted in rapid induction of apoptosis as indicated by caspase activation, phosphatidylserine exposure, mitochondrial alterations and morphological changes. Addition of the antioxidants alpha-tocopherol acetate effectively inhibited the CD437-induced apoptosis. Measurement of the intracellular free radicals indicated a rise in oxidative stress in CD437-treated cells, which could be attenuated by alpha-tocopherol acetate. Interestingly, pretreatment of cells with the cathepsin D inhibitor pepstatin A blocked the CD437-induced free radical formation and apoptotic effects, suggesting the involvement of cathepsin D. However, Western blotting revealed no difference in cellular quantity of any forms of cathepsin D between control cells and CD437-treated cells, whereas immunofluorescence analysis of the intracellular distribution of cathepsin D showed release of the enzyme from lysosomes to the cytosol. Labeling of lysosomes with lysosomotropic probes confirmed that CD437 could induce lysosomal leakage. The CD437-induced relocation of cathepsin D could not be prevented by alpha-tocopherol acetate, suggesting that the lysosomal leakage precedes free radical formation. Furthermore, a retinoic acid nuclear receptor (RAR) antagonist failed to block these effects of CD437, suggesting that the action of CD437 is RAR-independent. Taken together, these data suggest a novel lysosomal pathway for CD437-induced apoptosis, in which lysosomes are the primary target and cathepsin D and free radicals act as death mediators.
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PMID:Evidence of a lysosomal pathway for apoptosis induced by the synthetic retinoid CD437 in human leukemia HL-60 cells. 1142 8

Alternative splicing of precursor mRNA is a fundamental mechanism to generate multiple proteins from a single gene. Although constitutive and alternative mRNA splicing is temporally and spatially regulated, deregulation of mRNA splicing could cause development, progression, and metastasis of tumors. Through yeast two-hybrid screening of a human breast cDNA library using estrogen receptor-alpha (ERalpha) as bait, we identified a novel nuclear receptor box containing full-length protein, nuclear protein E3-3 (NPE3-3). Our results revealed that NPE3-3 associates with not only ERalpha but also with splicing factors, serine/arginine-rich protein (SRp)-30c, SRp40, and splicing factor SC-35, suggesting that NPE3-3 is likely to be involved in regulation of mRNA splicing. Accordingly, transient expression of NPE3-3 in cells resulted in expected splicing of the CD44 control minigene. We also discovered that NPE3-3-overexpressing clones produced a novel, previously unrecognized, alternatively spliced variant of ERalpha (termed ERalphaV), which had a molecular size of 37 kDa composed of only exons 1, 2, 7, and 8. ERalphaV was expressed and sequestered in the cytoplasm in MCF-7 cells stably overexpressing NPE3-3, suggesting its involvement in nongenomic hormone signaling. NPE3-3 clones exhibited up-regulation of ERK1/2 signaling, cyclin D1, and cathepsin D and enhanced tumor cell proliferation, migration, and tumorigenicity. Moreover, direct expression of the ERalphaV in breast cancer cells stimulated ERK1/2 up-regulation and cyclin D1 expression. We found that ERalphaV physically interacted with MAPK kinase (MEK)-1/2, and thus, an ERalphaV and MEK1/2 complex could lead to the activation of the ERK1/2 pathway. Interestingly, NPE3-3 was up-regulated in human breast tumors. These findings revealed a role for NPE3-3 in alternative splicing and suggest that ERalpha is a physiological target of NPE3-3, leading to a constitutive nongenomic signaling pathway in breast cancer cells.
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PMID:Identification of a novel estrogen receptor-alpha variant and its upstream splicing regulator. 2030 96