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[apoptosis-related protein in the TGF-beta signaling pathway] This protein is the product of a human gene that is the counterpart of the murine septin H5 (also: Bh5 [Brain protein 5) (Larisch et al, 2000). It has been described independently as PNUTL-2 (peanut-like-2) (Paavola et al, 1999), a protein of 478 amino acids that contains a GTP binding domain and that is the human counterpart of the Drosophila melanogaster gene peanut. ARTS has been described independently as Bradeion. The protein is being referred to also as septin H5. Databank synonyms are also CEP7 [Cerebral protein 7] and CDCREL-2 [Cell division control-related protein 2]. The approved gene symbol is SEPT4 [septin 4].

Zieger et al (2000) have described the existence of splice variants. Takahashi et al (2003) have described the same protein as M-septin (septin M), a major, alternatively spliced variant of the H5 gene in developing mouse brain. The expression of M-septin is upregulated during the neuronal differentiation of embryonal carcinoma P19 cells and has been shown to interact with Collapsin response mediator proteins, which have been implicated in axon guidance and outgrowth during neural development.

ARTS is expressed in many different cell types. Larisch et al (2000) have reported that ARTS enhances cell death by apoptosis induced by TGF-beta and some other agents inducing apoptosis, including arabinoside, etoposide, staurosporine and FAS). This process involves activation of caspase-3. ARTS is localized in mitochondria and translocates to the nucleus in dying cells. Gottfried et al (2004) and Bornstein et al (2011) have reported that ARTS promotes apoptosis through targeting the apoptosis inhibitor XIAP. Garrison et al (2011) have reported that ARTS serves as an adaptor to bridge E3 ligase Siah-1 [seven in absentia homolog 1] to induce ubiquitination and degradation of XIAP. ARTS initiates the mitochondrial apoptotic pathway upstream of cytochrome C and SMAC (Bornstein et al, 2011). Peptides mimicking the unique binding site between ARTS and XIAP have been shown to promote cell death by apoptosis in cultured cancer cells (Edison et al, 2012).

Larisch-Bloch et al have reported that ARTS can function as a tumor suppressor. In more than 70 % of acute lymphoblastic leukemia patients ARTS expression is lost (Elhasid et al, 2004). Tanaka et al (2002) have reported that the impaired expression of ARTS inhibits the growth and tumorigenesis of colorectal cancer in vitro and in vivo. Shen et al (2012) have shown that over-expression of ARTS in hepatocellular carcinoma cells sensitizes them to serum starvation-induced apoptosis, whereas a knock-down of ARTS expression rescues cells from apoptosis induced by serum deprivation and also promotes cell growth. ARTS expression is downregulated significantly in human hepatocellular carcinoma tissues.

Deletion of the ARTS gene in mice has been shown to promote the spontaneous development of tumors as a result of impaired apoptosis of stem cells and progenitor cells. The apoptosis, stem cell and tumor phenotypes of knock-out mice lacking expression of ARTS can be suppressed by inactivation of XIAP, demonstrating that ARTS acts mainly by targeting XIAP in vivo (Garcia-Fernandez et al, 2010).

Iwaisako et al (2008) have implicated ARTS in liver fibrosis. In vitro, ARTS expression downregulated in hepatic stellate cells when these cells transdifferentiate into myofibroblasts. Hepatic stellate cells from ARTS knock-out mice show normal morphology and proliferation, but transdifferentiation itno myofibroblasts is accelerated. In vivo, liver fibrosis, which is associated with myofibroblast transdifferentiation of hepatic stellate cells, is more severe in ARTS knock-out mice than in wild-type littermates. Yanagida et al (2011) have reported that a reduced expression of the Wnt antagonist dkk-2 and a concomitant activation of canonical Wnt signaling links the loss of ARTS and myofibroblast transdifferentiation of hepatic stellate cells during liver fibrosis.

Ihara et al (2007) have suggested an involvement of ARTS in Parkinson's disease as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.

For other entries pertaining to cell death mechanisms see also the Apoptosis and Cell Death Dictionary section of this encyclopedia.

Copyright 2012 by H IBELGAUFTS. All rights reserved.


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