Distinct functions of H-Ras and K-Ras in proliferation and survival of primary hepatocytes due to selective activation of ERK and PI3K

✍ Scribed by Carola M. Rosseland; Lene Wierød; Liv I. Flinder; Morten P. Oksvold; Ellen Skarpen; Henrik S. Huitfeldt

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 400 KB
• Volume: 215
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21367

✦ Synopsis

Abstract

Ras proteins mediate signals both via extracellular signal‐regulated kinase 1 and 2 (ERK), and phosphoinositide 3‐kinase (PI3K). These signals are key events in cell protection and compensatory cell growth after exposure to cell damaging and pro‐apoptotic stimuli, thus maintaining homeostasis. By transfection techniques, we found that both H‐Ras and K‐Ras were expressed and appeared functionally active in primary hepatocytes. We compared the ability of H‐Ras and K‐Ras homologues to preferentially activate one of the two pathways, thereby differentially controlling cell survival and growth. We found that ectopic expression of dominant negative (DN) H‐RasN17, but not DN K‐RasN17, efficiently inhibited both phosphorylation and translocation of ERK to the nuclear compartment, which are prerequisites for cell cycle progression. Furthermore, ectopic expression of constitutive active (CA) H‐RasV12, but not CA K‐RasV12, potentiated EGF‐induced proliferation. We also found that expression of CA mutants of either H‐Ras or K‐Ras protected hepatocytes from transforming growth factor‐β1 (TGF‐β1)‐induced apoptosis. However, H‐Ras‐induced survival was mediated by ERK/RSK as well as by PI3K, whereas K‐Ras‐induced survival was mediated by PI3K only. In conclusion, H‐Ras and K‐Ras had differential functions in proliferation and survival of primary hepatocytes. H‐Ras was the major mediator of ERK‐induced proliferation and survival, whereas H‐Ras and K‐Ras both mediated PI3K‐induced survival. J. Cell. Physiol. 215: 818–826, 2008. © 2007 Wiley‐Liss, Inc.