Abstract
Expression of the GTPase-deficient, activated mutant α-subunit of the heterotrimeric G protein G12 (Gα12QL) leads to the neoplastic transformation of fibroblast cell lines. The mitogenic pathway regulated by Gα12QL includes an extensive signaling network involving several small GTPases and various kinases. In addition, Gα12QL has been shown to potentiate the serum-induced phospholipase-A2 activity in NIH3T3 cells. In the present study, we demonstrate that cycloxygenase-2 (COX-2) pathway is involved in the mitogenic pathway activated by Gα12QL. Expression of Gα12QL and not Gα13QL, stimulates the serum-induced release of arachidonic acid in NIH3T3 cells. Furthermore, expression of Gα12QL or the stimulation of wild-type Gα12 induces the expression of COX-2. Our results also indicate that the COX-2 inhibitor acutely disrupts the DNA-synthesis stimulated by Gα12QL in NIH3T3 cells. These studies, for the first time, identify the crucial role of COX-2 in Gα12-mediated regulation of cell proliferation and suggest a role for prostaglandin-derived autocrine loop in Gα12-mediated signaling pathways.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aragay AM, Collins LR, Post GR, Watson AJ, Feramisco JR, Brown JH and Simon MI. . 1995 J. Biol. Chem. 270: 20073–20077.
Buhl AM, Lassignal-Johnson N, Dhanasekaran N and Johnson GL. . 1995 J. Biol. Chem. 270: 24631–24634.
Chan AM-L, Fleming TP, McGovern ES, Chedid M, Miki T and Aaronson SA. . 1993 Mol. Cell. Biol. 13: 762–768.
Collins LR, Minden A, Karin M and Brown JH. . 1996 J. Biol. Chem. 271: 17349–17353.
Dennis EA. . 1997 Trends Biochem. Sci. 22: 1–2.
Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB and Lipsky PE. . 1998 FASEB J. 12: 1063–1073.
Dhanasekaran N and Dermott JM. . 1996 Cell Signaling. 8: 235–234.
Dhanasekaran N, Tsim S-T, Dermott JM and Onesime D. . 1998 Oncogene 17: 1383–1394.
Fromm C, Coso OA, Montaner S, Xu N and Gutkind JS. . 1997 Proc. Natl. Acad. Sci. USA 94: 10098–10103.
Gebauer G, Peter AT, Onesime D and Dhanasekaran N. . 1999 J. Cell. Biochem. 75: 547–554.
Heasley LE, Thaler S, Nicks M, Price B, Skorecki K and Nemenoff RA. . 1997 J. Biol. Chem. 272: 14501–14504.
Herschman HR. . 1994 Cancer Metastasis Rev. 13: 241–256.
Hooley R, Yu C-Y, Symons M and Barber DL. . 1996 J. Biol. Chem. 271: 6152–6158.
Jiang H, Wu D and Simon MI. . 1993 FEBS Lett. 3: 319–322.
Kujubu DA, Fletcher BS, Varnum BC, Lim RW and Herschman HR. . 1991 J. Biol. Chem. 266: 12866–12872.
Leslie CC. . 1997 J. Biol. Chem. 272: 16709–16712.
Needham LK and Rozengurt E. . 1998 J. Biol. Chem. 273: 14626–16632.
Penning TD, Talley JJ, Bertenshaw SR, Carter JS, Collins PW, Docter S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers RS, Rogier DJ, Yu SS, Anderson GD, Burton EG, Cogburn JN, Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen AW, Zhang YY and Isakson PC. . 1997 J. Med. Chem. 40: 1347–1365.
Reddy ST and Herschman HR. . 1994 J. Biol. Chem. 269: 15473–15480.
Slice LW, Walsh JH and Rozengurt E. . 1999 J. Biol. Chem. 274: 27562–27566.
Tolkacheva T, Feuer B, Lorenzi MV, Saez R and Chan AM-L. . 1997 Oncogene 15: 727–735.
Tsujii M, Kawano S and DuBois RN. . 1997 Proc. Natl. Acad. Sci. USA 94: 3336–3340.
Vane JR, Bakhle YS and Botting RM. . 1998 Annu. Rev. Pharmacol. Toxicol. 38: 97–120.
Vara Prasad MVVS, Dermott JM, Heasley LE, Johnson GL and Dhanasekaran N. . (1995) J. Biol. Chem. 270: 18655–18659.
Vara Prasad M, Shore SK and Dhanasekaran N. . 1994 Oncogene 9: 2425–2429.
Voyno-Yasenetskaya TA, Faure MP, Ahn NG and Bourne HR. . 1996 J. Biol. Chem. 271: 21081–21087.
Voyno-Yasenetskaya T, Pace AM and Bourne HR. . 1994 Oncogene 9: 2559–2565.
Xu N, Bradley L, Ambudkar I and Gutkind JS. . 1993 Proc. Natl. Acad. Sci. USA 90: 11354–11358.
Xu N, Voyno-Yasenetskaya T and Gutkind JS. . 1994 Biochem, Biophys. Res. Comm. 201: 603–609.
Zhang Y, Saez R, Leal MA and Chan AM-L. . 1996 Oncogene 12: 2377–2383.
Acknowledgements
This work was supported by National Institutes of Health Grant GM 49897 (N Dhanasekaran).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Dermott, J., Reddy, M., Onesime, D. et al. Oncogenic mutant of Gα12 stimulates cell proliferation through cycloxygenase-2 signaling pathway. Oncogene 18, 7185–7189 (1999). https://doi.org/10.1038/sj.onc.1203345
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203345
Keywords
This article is cited by
-
The emerging roles of Gα12/13 proteins on the hallmarks of cancer in solid tumors
Oncogene (2022)
-
G protein alpha 12
AfCS-Nature Molecule Pages (2010)
-
Gα13 regulates MEF2-dependent gene transcription in endothelial cells: role in angiogenesis
Angiogenesis (2009)
-
Interaction between cyclooxygenase-2 gene polymorphism and dietary n-6 polyunsaturated fatty acids on colon cancer risk: The Singapore Chinese Health Study
British Journal of Cancer (2004)
-
Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?
British Journal of Cancer (2003)