MRG1, the product of a melanocyte-specific gene related gene, is a cytokine-inducible transcription factor with transformation activity

Abstract

Identification of cytokine-inducible genes is imperative for determining the mechanisms of cytokine action. A cytokine-inducible gene, mrg1 [melanocyte-specific gene (msg1) related gene], was identified through mRNA differential display of interleukin (IL) 9-stimulated and unstimulated mouse helper T cells. In addition to IL-9, mrg1 can be induced by other cytokines and biological stimuli, including IL-1␣, -2, -4, -6, and -11, granulocyte͞macrophage colonystimulating factor, interferon ␥, platelet-derived growth factor, insulin, serum, and lipopolysaccharide in diverse cell types. The induction of mrg1 by these stimuli appears to be transient, with induction kinetics similar to other primary response genes, implicating its role in diverse biological processes. Deletion or point mutations of either the Box1 motif (binds Janus kinase 1) or the signal transducer and activator of transcription 3 binding site-containing region within the intracellular domain of the IL-9 receptor ligand binding subunit abolished or greatly reduced mrg1 induction by IL-9, suggesting that the Janus kinase͞signal transducer and activator of transcription signaling pathway is required for mrg1 induction, at least in response to IL-9. Transfection of mrg1 cDNA into TS1, an IL-9-dependent mouse T cell line, converted these cells to IL-9-independent growth through a nonautocrine mechanism. Overexpression of mrg1 in Rat1 cells resulted in loss of cell contact inhibition, anchorageindependent growth in soft agar, and tumor formation in nude mice, demonstrating that mrg1 is a transforming gene. MRG1 is a transcriptional activator and may represent a founding member of an additional family of transcription factors.

Cited2 modulates TGF-β-mediated upregulation of MMP9

“…Although Cited2 is a transforming gene, as we previously showed, and overexpression of Cited2 in Rat1 cells causes tumor formation in nude mice (Sun et al, 1998), the mechanism involved in tumor formation was unclear. Our current demonstration that Cited2 modulates TGF-b-mediated upregulation of MMP9 and enhances in vitro tumor cell invasion may in part explain why overexpression of Cited2 promotes tumor formation in nude mice.…”

“…The Cited (CBP/p300-interacting transactivators with glutamic acid (E)/aspartic acid (D)-rich C-terminal domain) gene family consists of four nuclear proteins -Cited1 (formerly MSG1) (Shioda et al, 1996(Shioda et al, , 1997Dunwoodie et al, 1998), Cited2 (formerly MRG1/ p35srj) (Shioda et al, 1997;Dunwoodie et al, 1998;Sun et al, 1998;Bhattacharya et al, 1999;Leung et al, 1999), Cited3 (Andrews et al, 2000), and Cited4 (formerly MRG2) (Braganca et al, 2002). Members of this family function as transcriptional co-activators without classical DNA-binding domains.…”

“…Transcriptional responses by Cited2 can be enhanced through its association with nuclear receptors, such as peroxisome proliferator activated receptor (PPAR), to enhance transcription of target genes (Tien et al, 2004). Cited2 expression is induced by many cytokines and biological stimuli, including IL-1a, -2, -4, -6, -9 and -11, granulocyte/macrophage colony-stimulating factor, interferon-g, platelet-derived growth factor, insulin, serum, lipopolysaccharide, and hypoxia in diverse cell types (Sun et al, 1998;Bhattacharya et al, 1999).…”

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

“…48,49 As a member of the CITED family of transcriptional co-activators, the promoter of CITED2 contains multiple STAT-binding sites, consistent with its responsiveness to different cytokines. 50,51 In addition, crosstalk between the IFN-a system and a member of the nuclear hormone receptor-peroxisome proliferator-activated receptor a (PPARa) is suggested by CITED2, which is a known PPARa co-activator. 52 The PPARs have been implicated in a wide range of biological processes, including cell growth, lipid homeostasis, apoptosis and inflammation.…”

Cited2 is required for normal hematopoiesis in the murine fetal liver

“…1 Cited2 (cAMP-responsive element-binding protein [CBP]/p300-interacting transactivators with glutamic acid [E] and aspartic acid [D]-rich tail 2) is one of the founding members of a new family of transcriptional modulators. [2][3][4][5] As a CBP/p300-dependent transcription factor, Cited2 binds directly with high affinity to the first cysteine-histidine-rich (CH1) region of p300 and CBP. 6 Cited2 is induced by many biologic stimuli, such as cytokines, serum, and lipopolysaccharide, in different cell types.…”