Disease relevance of ERRFI1

• Moreover, germline disruption of Mig-6 in mice leads to the development of animals with epithelial hyperplasia, adenoma, and adenocarcinoma in organs like the lung, gallbladder, and bile duct [1].
• Mitogen-inducible gene 6 (MIG-6) is located in human chromosome 1p36, a locus frequently associated with human lung cancer [1].
• Herein, we have addressed tumor suppression by RALT/MIG-6, a transcriptionally controlled feedback inhibitor of ErbB RTKs, in breast cancer cells [2].
• Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin [2].
• Two H4IIE hepatoma cell genes, phosphoenolpyruvate carboxykinase (PEPCK) and gene 33 (g33), are reciprocally regulated by insulin [3].

High impact information on ERRFI1

• Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation [4].
• Mig6 functions in cells of hepatic origin and in neurons, which suggests a role for Mig6 in different cell lineages [5].
• This interaction was reproduced in vitro with a glutathione S-transferase fusion protein spanning positions 282 to 395 of the 459-residue gene 33 protein [6].
• We find that mig-6 is constitutively expressed in many human cancer cell lines, and Mig-6 is cleaved into the NH(2)-terminal region containing the CRIB domain and the remainder of the COOH-terminal region by limited proteolytic processing [7].
• These findings suggest that the processed CRIB domain of Mig-6 will compete with NFkappaB for IkappaBalpha and result in NFkappaB activation [7].

Biological context of ERRFI1

• Whereas the deleterious effects of chronic stress are well established, the molecular mechanisms by which these stresses affect cell function are still poorly characterized. gene 33 (also called mitogen-inducible gene-6, mig-6) is an immediate early gene that is transcriptionally induced by a divergent array of extracellular stimuli [8].
• Dex induces Gene 33 expression and inhibits EGFR phosphorylation and EGF signaling [9].
• Evidence that MIG-6 is a tumor-suppressor gene [1].
• Conversely, knockdown of RALT by RNA interference enhanced ErbB mitogenic signalling [10].
• A RALT transgene driven by the K14 promoter generated a dose-dependent phenotype resembling that caused by hypomorphic and antimorphic Egfr alleles-that is, wavy coat, curly whiskers and open eyes at birth [10].

Anatomical context of ERRFI1

• Ex vivo keratinocytes from K14-RALT mice showed reduced biochemical and biological responses when stimulated by ErbB ligands [10].
• Knockdown of RALT expression by RNAi enhanced the EGF-dependent proliferation of normal breast epithelial cells, indicating that loss of RALT signalling in breast epithelium may represent an advantageous condition during ErbB-driven tumorigenesis [2].
• However, the precise role of Mig-6 has virtually been a mystery until recently, when we and others discovered that Mig-6 may play important roles in regulating stress response, maintaining homeostasis in tissues like joints or cardiac muscle, and functioning as a tumor suppressor [11].
• Induction of MIG-6 by MMS was found in human diploid skin fibroblasts and in simian virus 40-transformed skin fibroblasts, indicating that the enhanced expression of MIG-6 after MMS-treatment did not require p53 [12].

Associations of ERRFI1 with chemical compounds

• Reciprocal regulation of gene transcription by insulin. Inhibition of the phosphoenolpyruvate carboxykinase gene and stimulation of gene 33 in a single cell type [3].
• Induction of the SAPK activator MIG-6 by the alkylating agent methyl methanesulfonate [12].
• Previously, we found that Gene 33 expression is significantly induced by retinoic acid (RA), insulin and synergistically by both in a liver-derived cell line [13].

Regulatory relationships of ERRFI1

• However, epidermal growth factor (EGF) induced Gene 33 expression in SK-BR-3 cells and this induction was inhibited by co-treatment with RA [13].
• We previously demonstrated that Mig-6 expression is induced by activated Ki-ras in human colon cancer cells and the limited proteolytic processed NH(2)-terminal region containing the Cdc42/Rac interaction and binding (CRIB) domain of Mig-6 is bound to IkappaBalpha, resulting in NF-kappaB activation [14].

Other interactions of ERRFI1

• This expression pattern suggests that gene 33 is a potential marker for diabetic nephropathy and other pathologic responses to persistent sublethal stress [8].
• Reconstitution of RALT expression in ERBB2-amplified SKBr-3 and BT474 cells inhibited ErbB-2-dependent mitogenic signalling and counteracted the ability of ErbB ligands to promote resistance to the ErbB-2-targeting drug Herceptin [2].
• Gene33 protein possesses binding domains for ErbB receptors, 14-3-3 proteins, SH-3 domains, and GTP bound Cdc42, suggesting that it may play a role in signal transduction [15].
• In growth-arrested cells, expression of endogenous RALT is induced by mitogenic stimuli, is high throughout mid to late G1 and returns to baseline as cells move into S phase [16].
• Inhibition of phosphatidylinositol 3-kinase (PI3-K) activity alone did not significantly alter transcription of Gene33 [17].

Analytical, diagnostic and therapeutic context of ERRFI1

• We propose that the gene 33 protein be renamed with the acronym RALT (receptor-associated late transducer) [6].
• The expression of these proteins was compared to the level of endogenous Gene33 by Western blot using a newly developed polyclonal antibody [15].
• One of these genes, MIG-6/gene 33, was chosen for verification by real- time quantitative reverse transcriptase polymerase chain reaction (RT-PCR) [18].

References