Oncogenic K-Ras and Basic Fibroblast Growth Factor Prevent Fas-mediated Apoptosis in Fibroblasts through Activation of Mitogen-activated Protein Kinase

doi:10.1083/jcb.148.3.557

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© The Rockefeller University Press, 0021-9525/2000/2/557/ $5.00
The Journal of Cell Biology, Volume 148, Number 3, February 7, 2000 557-566

Original Article

Oncogenic K-Ras and Basic Fibroblast Growth Factor Prevent Fas-mediated Apoptosis in Fibroblasts through Activation of Mitogen-activated Protein Kinase

Hirotaka Kazama^a and Shin Yonehara^a
^a Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan

Correspondence to: Shin Yonehara, Institute for Virus Research, Kyoto University, Shogoin Kawahara-cho 53, Sakyo-ku, Kyoto 606-8507, Japan. Tel:81-75-751-4783 Fax:81-75-751-4784 E-mail:syonehar{at}virus.kyoto-u.ac.jp.

By an expression cloning method using Fas-transgenic Balb3T3cells, we tried to obtain inhibitory genes against Fas-mediatedapoptosis and identified proto-oncogene c-K-ras. Transient expressionof K-Ras mutants revealed that oncogenic mutant K-Ras (RasV12)strongly inhibited, whereas dominant-inhibitory mutant K-Ras(RasN17) enhanced, Fas-mediated apoptosis by inhibiting Fas-triggeredactivation of caspases without affecting an expression levelof Fas. Among the target molecules of Ras, including Raf (mitogen-activatedprotein kinase kinase kinase [MAPKKK]), phosphatidylinositol3 (PI-3) kinase, and Ral guanine nucleotide exchange factor(RalGDS), only the constitutively active form of Raf (Raf-CAAX)could inhibit Fas-mediated apoptosis. In addition, the constitutivelyactive form of MAPKK (SDSE-MAPKK) suppressed Fas-mediated apoptosis,and MKP-1, a phosphatase specific for classical MAPK, canceledthe protective activity of oncogenic K-Ras (K-RasV12), Raf-CAAX,and SDSE-MAPKK. Furthermore, physiological activation of Rasby basic fibroblast growth factor (bFGF) protected Fas-transgenicBalb3T3 cells from Fas-mediated apoptosis. bFGF protection wasalso dependent on the activation of the MAPK pathway throughRas. All the results indicate that the activation of MAPK throughRas inhibits Fas-mediated apoptosis in Balb3T3 cells, whichmay play a role in oncogenesis.

Key Words: basic fibroblast growth factor, Fas, mitogen-activated proteinkinase, oncogenesis, Ras

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