Lyn regulates the cell death response to ultraviolet radiation through c-Jun N terminal kinase-dependent Fas ligand activation.
The Src-related tyrosine kinase, Lyn, plays an important role in mediating the cell cycle arrest and cell death response to genotoxic agents such as ionizing radiation. In this report we provide evidence to show that the catalytic function of Lyn is required for ultraviolet radiation (UV)- and methyl methanesulfonate (MMS)- but not for cisplatin (CDDP)- or ionizing radiation (IR)-induced cell death. Consequently, fibroblasts deficient in Lyn function were protected against cell death induction by UV and MMS, but showed normal cell death to IR and CDDP treatment. In Lyn(-/-) cells, UV-induced activation of stress-responsive kinases, Erk1/2 and p38, was normal; however, JNK activation was diminished. In addition, FasL induction by UV was also diminished in these cells. Reintroduction of wild-type Lyn restored JNK activation, FasL induction, and sensitivity to UV and MMS. A role for FasL in the cell death induction by Lyn-JNK signaling is indicated by the inhibition of cell death response by FasL neutralizing antibody. Together, the results support the presence of the Lyn-JNK signaling pathway that mediates the cell death response to UV and MMS treatment through FasL induction.
Shangary
Sanjeev
S
Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Lerner
Edwina C
EC
Zhan
Qimin
Q
Corey
Seth J
SJ
Smithgall
Thomas E
TE
Baskaran
R
R
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D016923:Cell Death / Q000502:physiology / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology / Q000528:radiation effects; D005057:Eukaryotic Cells / Q000201:enzymology* / Q000528:radiation effects; D053222:Fas Ligand Protein; D005333:Fetus; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000528:radiation effects; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000528:radiation effects; D011839:Radiation, Ionizing; D014466:Ultraviolet Rays / Q000009:adverse effects*; D019061:src-Family Kinases / Q000378:metabolism* / Q000528:radiation effects
D018906:Antineoplastic Agents, Alkylating; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D008741:Methyl Methanesulfonate; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D002945:Cisplatin