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Updated: Jul 11, 2026
Inducible and Reversible Dominant-negative (DN) Protein Inhibition
Published on: January 7, 2019
Tumor suppressive protein gene associated with retinoid-interferon-induced mortality (GRIM)-19 inhibits src-induced
Sudhakar Kalakonda1, Shreeram C Nallar, Ping Gong
1Department of Microbiology and Immunology, Greenebaum Cancer Center, University of Maryland School of Medicine, 660 West Redwood St., Howard Hall 350, Baltimore, MD 21201, USA.
Abstract:
Interferons (IFNs) inhibit the growth of infectious pathogens and tumor development. Although IFNs are potent tumor suppressors, they modestly inhibit the growth of some human solid tumors. Their weak activity against such tumors is augmented by co-treatment with differentiation-inducing agents such as retinoids. Previous studies from our laboratory identified a novel gene product, gene associated with retinoid-interferon-induced mortality (GRIM)-19, as an IFN/all-trans retinoic acid-induced growth suppressor. However, the mechanisms of its growth suppressive actions are unclear. The src-family of tyrosine kinases is important regulators of various cell growth responses. Mutational activation of src causes cellular transformation by altering transcription and cytoskeletal properties. In this study, we show that GRIM-19 suppresses src-induced cellular transformation in vitro and in vivo by down-regulating the expression of a number of signal transducer and activator of transcription-3 (STAT3)-dependent cellular genes. In addition, GRIM-19 inhibited the src-induced cell motility and metastasis by suppressing the tyrosyl phosphorylation of focal adhesion kinase, paxillin, E-cadherin, and gamma-catenin. Effects of GRIM-19 on src-induced cellular transformation are reversible in the presence of specific short hairpin RNA, indicating its direct effect on transformation. GRIM-19-mediated inhibition of the src-induced tyrosyl phosphorylation of cellular proteins, such as focal adhesion kinase and paxillin, seems to occur independently of the STAT3 protein. GRIM-19 had no significant effect on the cellular transformation induced by other oncogenes such as myc and Ha-ras. Thus, GRIM-19 not only blocks src-induced gene expression through STAT3 but also the activation of cell adhesion molecules.
Insights
Gene associated with retinoid-interferon-induced mortality (GRIM)-19 suppresses src-induced tumors by down-regulating STAT3-dependent genes and inhibiting cell motility. GRIM-19
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Interferons (IFNs) are potent tumor suppressors, but their efficacy against solid tumors is limited.
- Co-treatment with retinoids enhances IFN activity.
- GRIM-19 is a novel gene induced by IFN and retinoids, identified as a growth suppressor, but its mechanism is unclear.
Purpose of the Study:
- To elucidate the growth suppressive mechanisms of GRIM-19.
- To investigate GRIM-19's role in src-induced cellular transformation and metastasis.
Main Methods:
- Investigated GRIM-19's effect on src-induced cellular transformation in vitro and in vivo.
- Analyzed GRIM-19's impact on STAT3-dependent gene expression.
- Assessed GRIM-19's influence on cell motility and metastasis by examining protein phosphorylation.
- Utilized short hairpin RNA to confirm GRIM-19's direct effect on transformation.
Main Results:
- GRIM-19 suppresses src-induced cellular transformation and metastasis.
- GRIM-19 down-regulates STAT3-dependent gene expression.
- GRIM-19 inhibits src-induced cell motility by suppressing phosphorylation of focal adhesion kinase, paxillin, E-cadherin, and gamma-catenin.
- GRIM-19's inhibition of protein phosphorylation appears independent of STAT3.
Conclusions:
- GRIM-19 is a key suppressor of src-induced oncogenesis.
- GRIM-19 exerts its effects by inhibiting both STAT3-mediated gene expression and cell adhesion molecule activation.
- GRIM-19 represents a potential therapeutic target for src-driven cancers.
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