Oncogenic src, raf, and ras stimulate a hypertrophic pattern of gene expression and increase cell size in neonatal rat ventricular myocytes

Fuller, S. J., Gillespie-Brown, J. and Sugden, P. H. (1998) Oncogenic src, raf, and ras stimulate a hypertrophic pattern of gene expression and increase cell size in neonatal rat ventricular myocytes. Journal of Biological Chemistry, 273(29), pp. 18146-18152. (doi: 10.1074/jbc.273.29.18146)

Abstract

In response to hormones and growth factors, cultured neonatal ventricular myocytes increase in profile, exhibit myofibrillogenesis, and re-express genes whose expression is normally restricted to the fetal stage of ventricular development. These include atrial natriuretic factor (ANF), β-myosin heavy chain (β-MHC), and skeletal muscle (SkM)-α-actin. By using luciferase reporter plasmids, we examined whether oncogenes that activate the extracellular signal-regulated kinase cascade (src F527, Ha-ras V12, and v-raf) increased expression of “fetal” genes. Transfection of myocytes withsrc F527 stimulated expression of ANF, SkM-α-actin, and β-MHC by 62-, 6.7-, and 50-fold, respectively, but did not induce DNA synthesis. Stimulation of ANF expression bysrc F527 was greater than by Ha-ras V12, which in turn was greater than by v-raf. General gene expression was also increased but to a lesser extent. The response to src F527 was inhibited by dominant-negative Ha-ras N17. Myocyte area was increased by src F527, Ha-ras V12, and v-raf, and although it altered myocyte morphology by causing a pseudopodial appearance,src F527 did not detectably increase myofibrillogenesis either alone or in combination with Ha-ras V12. A kinase-dead src mutant increased myocyte size to a much lesser extent thansrc F527 and also did not inhibit ANF-luciferase expression in response to phenylephrine. We conclude that members of the Src family of tyrosine kinases may be important in mediating the transcriptional changes occurring during cardiac myocyte hypertrophy and that Ras and Raf may be downstream effectors.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Brown, Dr Judith
• Authors: Fuller, S. J., Gillespie-Brown, J., and Sugden, P. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
• Journal Name: Journal of Biological Chemistry
• Publisher: American Society for Biochemistry and Molecular Biology
• ISSN: 0021-9258
• ISSN (Online): 1083-351X