Opposite effects of Ha-Ras and Ki-Ras on radiation-induced apoptosis via differential activation of PI3K/Akt and Rac/p38 mitogen-activated protein kinase signaling pathways

Jung A. Choi, Moon Taek Park, Chang Mo Kang, Hong Duck Um, Sangwoo Bae, Kee Ho Lee, Tae Hwan Kim, Jae Hong Kim, Chul Koo Cho, Yun Sil Lee, Hee Yong Chung, Su Jae Lee

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53 Citations (Scopus)


It has been well known that Ras signaling is involved in various cellular processes, including proliferation, differentiation, and apoptosis. However, distinct cellular functions of Ras isozymes are not fully understood. Here we show the opposing roles of Ha-Ras and Ki-Ras genes in the modulation of cell sensitivity to ionizing radiation. Overexpression of active isoform of Ha-Ras (12V-Ha-Ras) in Rat2 cells increases resistance to the ionizing radiation. Constitutive activation of phosphoinositide-3-kinase (PI3K) and Akt is detected specifically in 12V-Ha-Ras-overexpressing cells. The specific PI3K inhibitor LY294002 inhibits PI3K/Akt signaling and potentiates the radiation-induced apoptosis, suggesting that activation of the PI3K/Akt signaling pathway is involved in the increased radio-resistance in cells overexpressing 12V-Ha-Ras. Overexpression of activated Ki-Ras (12V-Ki-Ras), on the other hand, markedly increases radiation sensitivity. The p38 mitogen-activated protein kinase (MAPK) activity is selectively enhanced by ionizing radiation in cells overexpressing 12V-Ki-Ras. The specific p38 MAPK inhibitor, PD169316, or dominant-negative p38 MAPK decreases radiation-induced cell death. We further show that the mechanism that underlies potentiation of cell death in cells overexpressing 12V-Ki-Ras involves Bax translocation to the mitochondrial membrane. Elevated Bax translocation following ionizing irradiation in 12V-Ki-Ras-overexpressing cells is completely inhibited by PD169316 or dominant-negative p38 MAPK. In addition, introduction of cells with RacN17, a dominant-negative mutant of Rac, resulted in a marked inhibition of radiation-induced Bax translocation and apoptotic cell death as well as p38 MAPK activation. Taken together, these findings explain the opposite effects of Ha-Ras and Ki-Ras on modulation of radiosensitivity, and suggest that differential activation of PI3K/Akt and Rac/p38 MAPK signaling by Ha-Ras and Ki-Ras may account for the opposing response to the ionizing radiation. These data provide an explanation for the diverse biological functions of Ras isozymes, and partly accounts for the differential response of transformed cells to anticancer treatments.

Original languageEnglish
Pages (from-to)9-20
Number of pages12
Issue number1
Publication statusPublished - 2004 Jan 8

Bibliographical note

Funding Information:
*Correspondence: S-J Lee, Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Gongneung-Dong, Nowon-Ku, Seoul 139-706, Korea; E-mail: sjlee@kcchsun.kcch.re.kr This work was supported by the Nuclear R&D Program of the Ministry of Science and Technology in Korea Received 15 April 2003; revised 6 July 2003; accepted 7 July 2003

Funding Information:
This work was supported by a Nuclear R&D Program from the Ministry of Science and Technology in Korea.


  • 12V-Ha-Ras
  • 12V-Ki-Ras
  • Bax translocation
  • PI3K/Akt
  • Rac/p38 MAPK
  • Radiation-induced apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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