A Specific Isozyme of 2′-5′ Oligoadenylate Synthetase Is a Dual Function Proapoptotic Protein of the Bcl-2 Family

Ghosh, Arundhati; Sarkar, Saumendra N.; Rowe, T.; Sen, Ganes C.

doi:10.1074/jbc.m100496200

Cited by 73 publications

(55 citation statements)

References 26 publications

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“…Importantly, we have found that Notch activation in keratinocytes causes selective suppression of some interferon-responsive genes, while inducing others (Supplementary Table 2), pointing to the existence of a novel mechanism for the fine tuning of the interferon response, which may be of particular significance for modulation of growth-differentiation control as opposed to the antiviral function. Several of the interferon-responsive genes under negative Notch control in keratinocytes have been previously implicated in positive growth control, apoptosis, and/or tumorigenesis (e.g., see Ghosh et al 2001;Carpten et al 2002;Wasylyk et al 2002;Zhang and Pagano 2002), with an impact that is likely to extend to keratinocytes. We note in particular the down-modulation of Sp100, a key component of nuclear bodies involved in chromatin control (Moller et al 2003), which parallels the opposite up-regulation of PML, another nuclear body component, in cells with loss of p63 expression (Bernassola et al 2005;Keyes et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Nguyen¹,

Lefort²,

Mandinova³

et al. 2006

Genes Dev.

341

411

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Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. Normal tissue homeostasis is determined by a complex interplay between developmental signals and other cell regulatory pathways. Notch cell surface receptors and their ligands belonging to the Delta and Serrate/Jagged families play a crucial role in cell fate determination and differentiation, functioning in a cell-and context-specific manner (Artavanis-Tsakonas et al. 1999). In mammalian cells, Notch activation is generally thought to maintain stem cell potential and inhibit differentiation, thereby promoting carcinogenesis (Artavanis-Tsakonas et al. 1999). However, in specific cell types such as keratinocytes, increased Notch activity causes exit from the cell cycle and commitment to differentiation (Lowell et al. 2000;Rangarajan et al. 2001;Nickoloff et al. 2002), whereas down-modulation or loss of Notch1 function promotes carcinogenesis (Talora et al. 2002;Nicolas et al. 2003).In the human epidermis, localized expression of the Notch-ligand Delta in putative "stem cells" has been proposed to induce commitment of neighboring Notch1-expressing keratinocytes to a "transit-amplifying" phenotype, through a negative feedback mechanism of lateral inhibition (Lowell et al. 2000). On the other hand, in both mouse and human epidermis, Jagged 1/2, Notch1, and Notch2 are coexpressed in differentiating keratinocytes of the supra-basal layers, consistent with a positive feedback loop between these molecules that serves to reinforce and synchronize Notch activation with differentiation (Luo et al. 1997;Rangarajan et al. 2001;Nickoloff et al. 2002).The best characterized "canonical" pathway of Notch activation involves proteolytic cleavage and translocation of the cytoplasmic domain of the receptor to the nucleus, where it associates with the DNA-binding protein RBP-J (CBF-1, CSL), converting it from a repressor

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Section: Discussionmentioning

confidence: 99%

Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation

Nguyen¹,

Lefort²,

Mandinova³

et al. 2006

Genes Dev.

341

411

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“…The first molecular clone for an OAS was obtained by Michel Revel's lab [10]. Biochemical characterization of OAS proteins by Ara Hovanessian's lab [11][12][13][14] and Ganes Sen's lab [15][16][17][18][19] and a crystal structure by Rune Hartmann and Vivien Yee (in collaboration with Ganes Sen and Just Justesen) [20] have led to functional and structural insight into the OAS family of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript.…”

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confidence: 99%

A scientific journey through the 2-5A/RNase L system

Silverman

2007

Cytokine & Growth Factor Reviews

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The antiviral and antitumor actions of interferons are caused, in part, by a remarkable regulated RNA cleavage pathway known as the 2-5A/RNase L system. 2′-5′ linked oligoadenylates (2-5A) are produced from ATP by interferon-inducible synthetases. 2-5A activates pre-existing RNase L, resulting in the cleavage of RNAs within single-stranded regions. Activation of RNase L by 2-5A leads to an antiviral response, although precisely how this happens is a subject of ongoing investigations. Recently, RNase L was identified as the hereditary prostate cancer 1 gene. That finding has led to the discovery of a novel human retrovirus, XMRV. My scientific journey through the 2-5A system recounts some of the highlights of these efforts. Knowledge gained from studies on the 2-5A system could have an impact on development of therapies for important viral pathogens and cancer.Keywords 2-5A; RNase L; interferon; cancer; virus Background on the 2-5A/RNase L systemOver the past thirty-years, investigations into the mechanisms of interferon (IFN) action have elucidated how antiviral innate immunity operates within and between mammalian cells. The focus of my work over this period has been, and continues to be, probing the biology and biochemistry of the 2-5A/RNase L system, and studying its roles in health and disease. My scientific journey, from basic research to clinical studies, are summarized in this monograph. The 2-5A/RNase L system is one the principal pathways by which IFNs suppress viral infections. Exposure of cells to IFNs induces expression of genes that result in an "antiviral state". Type I IFNs bind to the IFN-α receptor 1 (IFNAR1) and IFNAR2 polypeptide chains on cell surfaces initiating JAK-STAT signaling to the IFN stimulated genes (ISGs) [1]. Included among over a hundred different ISGs are genes encoding 2-5A synthetases (OAS) [2,3]. The OAS genes are a family of ISGs that function in the 2-5A/RNase L system (Fig. 1). In humans there are three functional OAS genes (OAS1-3), resulting in 8 to 10 OAS isoforms due to alternative mRNA splicing [4]. In mice, in addition to OAS2 and OAS3 there are 7 separate OAS1 genes, including OAS1b, the flavivirus resistance gene (Flv r ] [5][6][7][8]. When stimulated by dsRNA, the functional OAS proteins produce a series of short 5′-phosphorylated, 2′,5′-linked oligoadenylates collectively referred to as 2-5A [p x 5′A(2′p5′A) n ; x = 1-3; n≥2] from ATP [9]. The first molecular clone for an OAS was obtained by Michel Revel's lab [10]. Biochemical characterization of OAS proteins by Ara Hovanessian's lab [11][12][13][14] and Ganes Sen's lab [15][16][17][18][19] and a crystal structure by Rune Hartmann and Vivien Yee (in collaboration with Ganes Sen and Just Justesen) [20] have led to functional and structural insight into the OAS family of Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, type...

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“…Both apoptosis and the antiviral effects of IFN against encephalomyocarditis virus are defective in RNase L Ϫ/Ϫ MEF cells and mutant mice devoid of RNase L (5). However, the 9-2 isoform of OAS1 shows comparable apoptotic activity in RNase L Ϫ/Ϫ cells as wild-type fibroblasts (15). It will be interesting to learn whether the presence or absence of RNase L affects the flavivirus resistance͞ susceptibility phenotype.…”

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confidence: 99%

“…That is, does the wild-type 1b͞L1 OAS protein in resistant mice have a dsRNA-independent function? Pertinent to this possibility, the 9-2 isoform of mouse OAS1 recently has been shown to be a dual-function protein that independently can synthesize 2-5A oligomers and promote cellular apoptosis (15). The proapoptotic activity, which is OAS-isoform specific, depends upon a functional Bcl-2 homology 3 domain present in the C-terminal region that interacts with the Bcl-2 and BclxL antiapoptotic proteins (15).…”

mentioning

confidence: 99%

“…Pertinent to this possibility, the 9-2 isoform of mouse OAS1 recently has been shown to be a dual-function protein that independently can synthesize 2-5A oligomers and promote cellular apoptosis (15). The proapoptotic activity, which is OAS-isoform specific, depends upon a functional Bcl-2 homology 3 domain present in the C-terminal region that interacts with the Bcl-2 and BclxL antiapoptotic proteins (15). Curiously, it is the C-terminal region of the OAS1 and OAS2 size class isoforms that are unique, in part because of alternative splicing (3,11).…”

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confidence: 99%

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