Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis

Oncogene volume 33, pages 3195–3204 (2014)Cite this article

Subjects

Abstract

The non-receptor tyrosine kinase Src is a major player in multiple physiological responses including growth, survival and differentiation. Overexpression and/or oncogenic mutation in the Src gene have been documented in human tumors. The v-Src protein is an oncogenic mutant of Src, which promotes cell survival, migration, invasion and division. GRIM-19 is an antioncogene isolated using a genome-wide knockdown screen. Genes associated with Retinoid-IFN-induced Mortality (GRIM)-19 binds to transcription factor STAT3 and ablates its pro-oncogenic effects while v-Src activates STAT3 to promote its oncogenic effects. However, we found that GRIM-19 inhibits the pro-oncogenic effects of v-Src independently of STAT3. Here, we report the identification of functionally inactivating GRIM-19 mutations in a set of head and neck cancer patients. While wild-type GRIM-19 strongly ablated v-Src-induced cell migration, cytoskeletal remodeling and tumor metastasis, the tumor-derived mutants (L71P, L91P and A95T) did not. These mutants were also incapable of inhibiting the drug resistance of v-Src-transformed cells. v-Src downregulated the expression of Pag1, a lipid raft-associated inhibitor of Src, which was restored by wild-type GRIM-19. The tumor-derived mutant GRIM-19 proteins failed to upregulate Pag1. These studies show a novel mechanism that deregulates Src activity in cancer cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Frame MC . Newest findings on the oldest oncogene; how activated src does it. J Cell Sci 2004; 117: 989–998.

    Article  CAS  PubMed  Google Scholar 

  2. Superti-Furga G, Fumagalli S, Koegl M, Courtneidge SA, Draetta G . Csk inhibition of c-Src activity requires both the SH2 and SH3 domains of Src. EMBO J 1993; 12: 2625–2634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hofmann ER, Boyanapalli M, Lindner DJ, Weihua X, Hassel BA, Jagus R et al. Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid. Mol Cell Biol 1998; 18: 6493–6504.

    Article  CAS  PubMed  Google Scholar 

  4. Angell JE, Lindner DJ, Shapiro PS, Hofmann ER, Kalvakolanu DV . Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-beta and retinoic acid combination, using a genetic approach. J Biol Chem 2000; 275: 33416–33426.

    Article  CAS  PubMed  Google Scholar 

  5. Zhang J, Yang J, Roy SK, Tininini S, Hu J, Bromberg JF et al. The cell death regulator GRIM-19 is an inhibitor of signal transducer and activator of transcription 3. Proc Natl Acad Sci USA 2003; 100: 9342–9347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT et al. GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. EMBO J 2003; 22: 1325–1335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stark GR, Darnell JE Jr . The JAK-STAT pathway at twenty. Immunity 2012; 36: 503–514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yu CL, Meyer DJ, Campbell GS, Larner AC, Carter-Su C, Schwartz J et al. Enhanced DNA-binding activity of a Stat3-related protein in cells transformed by the Src oncoprotein. Science 1995; 269: 81–83.

    Article  CAS  PubMed  Google Scholar 

  9. Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr . Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 1998; 18: 2553–2558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yu H, Pardoll D, Jove R . STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 2009; 9: 798–809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kalakonda S, Nallar SC, Gong P, Lindner DJ, Goldblum SE, Reddy SP et al. Tumor suppressive protein gene associated with retinoid-interferon-induced mortality (GRIM)-19 inhibits src-induced oncogenic transformation at multiple levels. Am J Pathol 2007; 171: 1352–1368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun P, Nallar SC, Kalakonda S, Lindner DJ, Martin SS, Kalvakolanu DV . GRIM-19 inhibits v-Src-induced cell motility by interfering with cytoskeletal restructuring. Oncogene 2009; 28: 1339–1347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mazurek S . Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 2011; 43: 969–980.

    Article  CAS  PubMed  Google Scholar 

  14. Oneyama C, Hikita T, Enya K, Dobenecker MW, Saito K, Nada S et al. The lipid raft-anchored adaptor protein Cbp controls the oncogenic potential of c-Src. Mol Cell 2008; 30: 426–436.

    Article  CAS  PubMed  Google Scholar 

  15. Byers LA, Sen B, Saigal B, Diao L, Wang J, Nanjundan M et al. Reciprocal regulation of c-Src and STAT3 in non-small cell lung cancer. Clin Cancer Res 2009; 15: 6852–6861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang XH, Wang Q, Gerald W, Hudis CA, Norton L, Smid M et al. Latent bone metastasis in breast cancer tied to Src-dependent survival signals. Cancer Cell 2009; 16: 67–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sabe H, Hata A, Okada M, Nakagawa H, Hanafusa H . Analysis of the binding of the Src homology 2 domain of Csk to tyrosine-phosphorylated proteins in the suppression and mitotic activation of c-Src. Proc Natl Acad Sci USA 1994; 91: 3984–3988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nada S, Yagi T, Takeda H, Tokunaga T, Nakagawa H, Ikawa Y et al. Constitutive activation of Src family kinases in mouse embryos that lack Csk. Cell 1993; 73: 1125–1135.

    Article  CAS  PubMed  Google Scholar 

  19. Alchanati I, Nallar SC, Sun P, Gao L, Hu J, Stein A et al. A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas. Oncogene 2006; 25: 7138–7147.

    Article  CAS  PubMed  Google Scholar 

  20. Liu YB, Shen WG, Ge H, Gai XD, Lu LL, Zhao XJ . [Expressions of survivin and GRIM-19 in prostate cancer]. Zhonghua nan ke xue 2011; 17: 21–26.

    PubMed  Google Scholar 

  21. Zhou Y, Li M, Wei Y, Feng D, Peng C, Weng H et al. Down-regulation of GRIM-19 expression is associated with hyperactivation of STAT3-induced gene expression and tumor growth in human cervical cancers. J Interferon Cytokine Res 2009; 29: 695–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhou AM, Zhao JJ, Ye J, Xiao WH, Kalvakolanu DV, Liu RY . Expression and clinical significance of GRIM-19 in non-small cell lung cancer. Ai Zheng 2009; 28: 431–435.

    CAS  PubMed  Google Scholar 

  23. Gong LB, Luo XL, Liu SY, Tao DD, Gong JP, Hu JB . Correlations of GRIM-19 and its target gene product STAT3 to malignancy of human colorectal carcinoma. Ai Zheng 2007; 26: 683–687.

    CAS  PubMed  Google Scholar 

  24. Zhang Y, Hao H, Zhao S, Liu Q, Yuan Q, Ni S et al. Downregulation of GRIM-19 promotes growth and migration of human glioma cells. Cancer Sci 2011; 102: 1991–1999.

    Article  CAS  PubMed  Google Scholar 

  25. Hynes RO . Integrins: bidirectional, allosteric signaling machines. Cell 2002; 110: 673–687.

    Article  CAS  PubMed  Google Scholar 

  26. Murphy DA, Courtneidge SA . The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function. Nat Rev Mol Cell Biol 2011; 12: 413–426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Weed SA, Parsons JT . Cortactin: coupling membrane dynamics to cortical actin assembly. Oncogene 2001; 20: 6418–6434.

    Article  CAS  PubMed  Google Scholar 

  28. Buday L, Downward J . Roles of cortactin in tumor pathogenesis. Biochim Biophys Acta 2007; 1775: 263–273.

    CAS  PubMed  Google Scholar 

  29. Li X, Zheng H, Hara T, Takahashi H, Masuda S, Wang Z et al. Aberrant expression of cortactin and fascin are effective markers for pathogenesis, invasion, metastasis and prognosis of gastric carcinomas. Int J Oncol 2008; 33: 69–79.

    PubMed  Google Scholar 

  30. Patel AS, Schechter GL, Wasilenko WJ, Somers KD . Overexpression of EMS1/cortactin in NIH3T3 fibroblasts causes increased cell motility and invasion in vitro. Oncogene 1998; 16: 3227–3232.

    Article  CAS  PubMed  Google Scholar 

  31. Li Y, Tondravi M, Liu J, Smith E, Haudenschild CC, Kaczmarek M et al. Cortactin potentiates bone metastasis of breast cancer cells. Cancer Res 2001; 61: 6906–6911.

    CAS  PubMed  Google Scholar 

  32. Yamada S, Yanamoto S, Kawasaki G, Mizuno A, Nemoto TK . Overexpression of cortactin increases invasion potential in oral squamous cell carcinoma. Pathol Oncol Res 2010; 16: 523–531.

    Article  CAS  PubMed  Google Scholar 

  33. Theocharis S, Klijanienko J, Giaginis C, Alexandrou P, Patsouris E, Sastre-Garau X . FAK and Src expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. J Cancer Res Clin Oncol 2012; 138: 1369–1377.

    Article  CAS  PubMed  Google Scholar 

  34. van Oijen MG, Rijksen G, ten Broek FW, Slootweg PJ . Overexpression of c-Src in areas of hyperproliferation in head and neck cancer, premalignant lesions and benign mucosal disorders. J Oral Pathol Med 1998; 27: 147–152.

    Article  CAS  PubMed  Google Scholar 

  35. Chen JY, Hung CC, Huang KL, Chen YT, Liu SY, Chiang WF et al. Src family kinases mediate betel quid-induced oral cancer cell motility and could be a biomarker for early invasion in oral squamous cell carcinoma. Neoplasia 2008; 10: 1393–1401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Koppikar P, Choi SH, Egloff AM, Cai Q, Suzuki S, Freilino M et al. Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma. Clin Cancer Res 2008; 14: 4284–4291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Matsouka PT, Flier JS . Relationship between c-src tyrosine kinase activity and the control of glucose transporter gene expression. Mol Endocrinol 1989; 3: 1845–1851.

    Article  CAS  PubMed  Google Scholar 

  38. White MK, Rall TB, Weber MJ . Differential regulation of glucose transporter isoforms by the src oncogene in chicken embryo fibroblasts. Mol Cell Biol 1991; 11: 4448–4454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Valle Casuso JC, Gonzalez-Sanchez A, Medina JM, Tabernero A . HIF-1 and c-Src mediate increased glucose uptake induced by endothelin-1 and connexin43 in astrocytes. PLoS One 2012; 7: e32448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Koppenol WH, Bounds PL, Dang CV . Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011; 11: 325–337.

    Article  CAS  PubMed  Google Scholar 

  41. Jiang LQ, Feng X, Zhou W, Knyazev PG, Ullrich A, Chen Z . Csk-binding protein (Cbp) negatively regulates epidermal growth factor-induced cell transformation by controlling Src activation. Oncogene 2006; 25: 5495–5506.

    Article  CAS  PubMed  Google Scholar 

  42. Fearnley IM, Carroll J, Shannon RJ, Runswick MJ, Walker JE, Hirst J . GRIM-19, a cell death regulatory gene product, is a subunit of bovine mitochondrial NADH:ubiquinone oxidoreductase (complex I). J Biol Chem 2001; 276: 38345–38348.

    Article  CAS  PubMed  Google Scholar 

  43. Huang G, Lu H, Hao A, Ng DC, Ponniah S, Guo K et al. GRIM-19, a cell death regulatory protein, is essential for assembly and function of mitochondrial complex I. Mol Cell Biol 2004; 24: 8447–8456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sena LA, Chandel NS . Physiological roles of mitochondrial reactive oxygen species. Mol Cell 2012; 48: 158–167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Giannoni E, Taddei ML, Chiarugi P . Src redox regulation: again in the front line. Free Radic Biol Med 2010; 49: 516–527.

    Article  CAS  PubMed  Google Scholar 

  46. Suzuki K, Oneyama C, Kimura H, Tajima S, Okada M . Down-regulation of the tumor suppressor C-terminal Src kinase (Csk)-binding protein (Cbp)/PAG1 is mediated by epigenetic histone modifications via the mitogen-activated protein kinase (MAPK)/phosphatidylinositol 3-kinase (PI3K) pathway. J Biol Chem 2011; 286: 15698–15706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lindner DJ, Borden EC, Kalvakolanu DV . Synergistic antitumor effects of a combination of interferons and retinoic acid on human tumor cells in vitro and in vivo. Clin Cancer Res 1997; 3: 931–937.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Michael Kahn (University of California at Los Angeles, CA) for lentiviral luciferase (pCCL-c-MNDU3c-Luc) vector. This study is supported by the National Institutes of Health grant CA105005 and an intramural award from the Cigarette restitution funds of the University of Maryland Greenebaum Cancer Center to DVK.

Author information

Author notes

  1. S Kalakonda and S C Nallar: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Microbiology & Immunology, Program in Oncology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA

    S Kalakonda, S C Nallar, P Sun & D V Kalvakolanu

  2. Taussig Cancer Center, Cleveland, OH, USA

    D J Lindner

  3. Head & Neck Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    R R Lorenz & E Lamarre

  4. Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    S P Reddy

Authors
  1. S Kalakonda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S C Nallar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D J Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R R Lorenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Lamarre
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S P Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D V Kalvakolanu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D V Kalvakolanu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kalakonda, S., Nallar, S., Lindner, D. et al. GRIM-19 mutations fail to inhibit v-Src-induced oncogenesis. Oncogene 33, 3195–3204 (2014). https://doi.org/10.1038/onc.2013.271

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2013.271

Keywords

Search

Advanced search

Quick links