Identification of a Structural Motif in the Tumor-suppressive Protein GRIM-19 Required for Its Antitumor Activity

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2010 Jul 3

PMID 20595633

Citations 4

Authors

Shreeram C Nallar

Sudhakar Kalakonda

Peng Sun

Yoshihiro Ohmori

Miki Hiroi

Kazumasa Mori

Daniel J Lindner

Dhananjaya V Kalvakolanu

Affiliations

Soon will be listed here.

Abstract

We have previously isolated GRIM-19, a novel growth suppressor, using a genetic method. GRIM-19 ablates cell growth by inhibiting the transcription factor signal transducer and activator of transcription 3 (STAT3). Up-regulation of STAT3 and growth promotion were observed in a number of human tumors. Although the tumor-suppressive actions of GRIM-19 are known, the structural elements required for its antitumor actions are not understood. Mutational and protein sequence analyses identified a motif in the N terminus of GRIM-19 that exhibited similarity to certain RNA viral proteins. We show that disruption of specific amino acids within this motif cripples the antitumor actions of GRIM-19. These mutants fail to interact with STAT3 efficiently and consequently do not inhibit growth-promoting gene expression. More importantly, we show that a clinically observed mutation in the N terminus of GRIM-19 also weakened its interaction with STAT3 and antitumor action. Together, these studies identify a major role for the N terminus of GRIM-19 in mediating its tumor-suppressive actions.

Citing Articles

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PMID: 35359604 PMC: 8962202. DOI: 10.3389/fmolb.2022.834814.

Heterogeneity of GRIM-19 Expression in the Adult Mouse Brain.

Hwang S, Kim J, Kim S Cell Mol Neurobiol. 2019; 39(7):935-951.

PMID: 31111264 PMC: 11457830. DOI: 10.1007/s10571-019-00689-1.

GRIM-19: A master regulator of cytokine induced tumor suppression, metastasis and energy metabolism.

Nallar S, Kalvakolanu D Cytokine Growth Factor Rev. 2016; 33:1-18.

PMID: 27659873 PMC: 5337140. DOI: 10.1016/j.cytogfr.2016.09.001.

Tumor-derived mutations in the gene associated with retinoid interferon-induced mortality (GRIM-19) disrupt its anti-signal transducer and activator of transcription 3 (STAT3) activity and promote oncogenesis.

Nallar S, Kalakonda S, Lindner D, Lorenz R, Lamarre E, Weihua X J Biol Chem. 2013; 288(11):7930-7941.

PMID: 23386605 PMC: 3597830. DOI: 10.1074/jbc.M112.440610.

GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis.

Shulga N, Pastorino J J Cell Sci. 2012; 125(Pt 12):2995-3003.

PMID: 22393233 PMC: 3434811. DOI: 10.1242/jcs.103093.

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