共查询到20条相似文献,搜索用时 5 毫秒
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The highly conserved Notch signaling pathway plays pleiotropic roles during embryonic development and is important for the
regulation of selfrenewing tissues. The physiological functions of this signaling cascade range from stem cell maintenance
and influencing cell fate decisions of barely differentiated progenitor cells, to the induction of terminal differentiation
processes, all of which have been found to be recapitulated in different forms of cancers. Although Notch signaling has mostly
been associated with oncogenic and growth-promoting roles, depending on the tissue type it can also function as a tumor suppressor.
Here we describe recent findings on Notch signaling in cancer and tumor angiogenesis, and highlight some of the therapeutic
approaches that are currently being developed to interfere with tumor growth and progression.
Received 2 April 2007; received after revision 29 June 2007; accepted 2 July 2007 相似文献
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Zolkiewska A 《Cellular and molecular life sciences : CMLS》2008,65(13):2056-2068
ADAM metalloproteases play important roles in development and disease. One of the key functions of ADAMs is the proteolytic processing of Notch receptors and their ligands. ADAM-mediated cleavage of Notch represents the first step in regulated intramembrane proteolysis of the receptor, leading to activation of the Notch pathway. Recent reports indicate that the transmembrane Notch ligands also undergo ADAM-mediated processing in cultured cells and in vivo. The proteolytic processing of Notch ligands modulates the strength and duration of Notch signals, leads to generation of soluble intracellular domains of the ligands, and may support a bi-directional signaling between cells. 相似文献
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A central mechanism in activation of the Notch signaling pathway is cleavage of the Notch receptor by ADAM metalloproteases. ADAMs also cleave Delta, the ligand for Notch, thereby downregulating Notch signals. Two ADAMs, Kuzbanian (Kuz) and TNF-alpha converting enzyme (TACE), are known to process both Delta and Notch, yet the role of these cleavages in signal propagation has remained controversial. Using an in vitro model, we show that Kuz regulates Notch signaling primarily by activating the receptor and has little overall effect on signaling via disabling Delta. We confirm that Kuz-dependent activation of Notch requires stimulation of Notch by Delta. However, over-expression of Kuz gives ligand-independent Notch activation. In contrast, TACE, which is elevated in expression in the developing Drosophila nervous system, can efficiently activate Notch in a ligand-independent manner. Altogether, these data demonstrate the potential for Kuz and TACE to participate in context- and mechanism-specific modes of Notch activation. 相似文献
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Jean-Leon Thomas Kasey Baker Jinah Han Charles Calvo Harri Nurmi Anne C. Eichmann Kari Alitalo 《Cellular and molecular life sciences : CMLS》2013,70(10):1779-1792
Notch cell interaction mechanism governs cell fate decisions in many different cell contexts throughout the lifetime of all Metazoan species. It links the fate of one cell to that of its neighbors through cell-to-cell contacts, and binding of Notch receptors expressed on one cell to their membrane bound ligands on an adjacent cell. Environmental cues, such as growth factors and extracellular matrix molecules, superimpose a dynamic regulation on this canonical Notch signaling pathway. In this review, we will focus on Notch signaling in the vertebrate vascular and nervous systems and examine its role in angiogenesis, neurogenesis, and neurovascular interactions. We will also highlight the molecular relationships of the Notch pathway with vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors, key regulators of both angiogenesis and neurogenesis. 相似文献
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Kateřina Vašíčková Peter Horak Petr Vaňhara 《Cellular and molecular life sciences : CMLS》2018,75(5):849-857
Two decades ago, following a systematic screening of LOH regions on chromosome 8p22, TUSC3 has been identified as a candidate tumor suppressor gene in ovarian, prostate and pancreatic cancers. Since then, a growing body of evidence documented its clinical importance in various other types of cancers, and first initial insights into its molecular function and phenotypic effects have been gained, though the precise role of TUSC3 in different cancers remains unclear. As a part of the oligosaccharyltransferase complex, TUSC3 localizes to the endoplasmic reticulum and functions in final steps of N-glycosylation of proteins, while its loss evokes the unfolded protein response. We are still trying to figure out how this mechanistic function is reconcilable with its varied effects on cancer promotion. In this review, we focus on cancer-related effects of TUSC3 and envisage a possible role of TUSC3 beyond endoplasmic reticulum. 相似文献
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Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers
has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to
form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic
synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts
with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite
catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to
form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating
mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by
the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative
diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases.
Received 4 September 2001; received after revision 28 November 2001; accepted 2 December 2001 相似文献
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Vimentin, a major constituent of the intermediate filament family of proteins, is ubiquitously expressed in normal mesenchymal
cells and is known to maintain cellular integrity and provide resistance against stress. Vimentin is overexpressed in various
epithelial cancers, including prostate cancer, gastrointestinal tumors, tumors of the central nervous system, breast cancer,
malignant melanoma, and lung cancer. Vimentin’s overexpression in cancer correlates well with accelerated tumor growth, invasion,
and poor prognosis; however, the role of vimentin in cancer progression remains obscure. In recent years, vimentin has been
recognized as a marker for epithelial–mesenchymal transition (EMT). Although EMT is associated with several tumorigenic events,
vimentin’s role in the underlying events mediating these processes remains unknown. By virtue of its overexpression in cancer
and its association with tumor growth and metastasis, vimentin serves as an attractive potential target for cancer therapy;
however, more research would be crucial to evaluate its specific role in cancer. Our recent discovery of a vimentin-binding
mini-peptide has generated further impetus for vimentin-targeted tumor-specific therapy. Furthermore, research directed toward
elucidating the role of vimentin in various signaling pathways would reveal new approaches for the development of therapeutic
agents. This review summarizes the expression and functions of vimentin in various types of cancer and suggests some directions
toward future cancer therapy utilizing vimentin as a potential molecular target. 相似文献
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Lage H 《Cellular and molecular life sciences : CMLS》2008,65(20):3145-3167
Although various mechanisms involved in anticancer multidrug resistance (MDR) can be identified, it remains a major problem
in oncology. Beyond that, the introduction of new “targeted” drugs have not solved the problem. On the contrary, it has been
demonstrated that the “classical” MDR-associated mechanisms are similar or identical to those causing resistance to these
novel agents. These mechanisms include the enhanced activity of drug pumps, i.e. ABC or alternative transporters; modulation
of cellular death pathways; alteration and repair of target molecules; and various less common mechanisms. Together they build
a complex network of cellular pathways and molecular mechanisms mediating an individual MDR phenotype. Although the application
of new high throughput “-omics” technologies have identified multiple new gene-/protein expression signatures or factors associated
with drug resistance, so far none of these findings has been useful for creating improved diagnostic assays, for prediction
of individual therapy response, or for development of updated chemosensitizers.
Received 05 March 2008; received after revision 21 May 2008; accepted 23 May 2008 相似文献
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Jessica L. Slack Corey P. Causey Paul R. Thompson 《Cellular and molecular life sciences : CMLS》2011,68(4):709-720
The recent approvals of anticancer therapeutic agents targeting the histone deacetylases and DNA methyltransferases have highlighted
the important role that epigenetics plays in human diseases, and suggested that the factors controlling gene expression are
novel drug targets. Protein arginine deiminase 4 (PAD4) is one such target because its effects on gene expression parallel
those observed for the histone deacetylases. We demonstrated that F- and Cl-amidine, two potent PAD4 inhibitors, display micromolar
cytotoxic effects towards several cancerous cell lines (HL-60, MCF7 and HT-29); no effect was observed in noncancerous lines
(NIH 3T3 and HL-60 granulocytes). These compounds also induced the differentiation of HL-60 and HT29 cells. Finally, these
compounds synergistically potentiated the cell killing effects of doxorubicin. Taken together, these findings suggest PAD4
inhibition as a novel epigenetic approach for the treatment of cancer, and suggest that F- and Cl-amidine are candidate therapeutic
agents for this disease. 相似文献
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