GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction

Abstract

Signal transducer and activator of transcription 3 (Stat3) is a latent cytoplasmic transcription factor that can be activated by cytokines and growth factors. Stat3 plays important roles in cell growth, anti-apoptosis and cell transformation, and is constitutively active in various cancers. We examined its potential regulators by yeast two-hybrid screening. GRIM-19, a gene product related to interferon-beta- and retinoic acid-induced cancer cell death, was identified and demonstrated to interact with Stat3 in various cell types. The interaction is specific for Stat3, but not for Stat1 and Stat5a. The interaction regions in both proteins were mapped, and the cellular localization of the interaction was examined. GRIM-19 itself co-localizes with mitochondrial markers, and forms aggregates at the perinulear region with co-expressed Stat3, which inhibits Stat3 nuclear translocation stimulated by epidermal growth factor (EGF). GRIM-19 represses Stat3 transcriptional activity and its target gene expression, and also suppresses cell growth in Src-transformed cells and a Stat3-expressing cell line. Our data suggest that GRIM-19 is a novel negative regulator of Stat3.

A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas

“…We have begun collecting more tumor tissues to address these questions. We and others have recently shown that GRIM-19 binds to STAT3 and inhibits its gene stimulating functions (Lufei et al, 2003;Zhang et al, 2003). In this regard, GRIM-19 appears to behave like the VHL protein, which binds to transcription factor HIF1 and prevents its gene stimulatory function (Iliopoulos et al, 1996;Maxwell et al, 1999).…”

Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-β and retinoic acid-induced cancer cell death

“…GRIM-19 was originally claimed as a nuclear protein, 10 but was later shown to be a mitochondrial protein. 11,12,14 In a recent review by Kalvakolanu, 34 it was proposed that GRIM-19 may initiate apoptosis, like cytochrome c and AIF, by translocation from the mitochondria to the nucleus upon IFN-b/RA stimulation. To test this hypothesis, we analyzed the cellular localization of GRIM-19, as well as other MRC subunit proteins, in the absence and presence of IFN-b/RA.…”

“…11 GRIM-19 was also identified as a negative regulator of signal transducer and activator of transcription (Stat)3. 12,13 To reveal its physiological role, we generated GRIM-19-deficient mice by gene targeting. 14 Although the deletion of GRIM-19 causes embryonic lethality, isolated GRIM-19 À/À blastocysts displayed abnormal mitochondrial structure and morphology.…”

Identification of alternatively spliced GRIM-19 mRNA in kidney cancer tissues

“…17 Furthermore, GRIM-19 has also been shown to repress the activity of the Signal Transducer and Activator of Transcription 3 (Stat3) and inhibit v-Src-induced oncogenic transformation and metastatic behavior of cells. 18,19 Thus, GRIM-19 is a good candidate gene to study the etiopathogenesis of mitochondrion-rich tumors.…”