Jun N-terminal kinase activity and early growth-response factor-1 gene expression are down-regulated in Fanconi anemia group A lymphoblasts.
Fanconi anemia (FA) is an autosomal recessive cancer susceptibility syndrome characterized by cellular sensitivity to genotoxic agents. In recent years, FA proteins have been associated with different molecules involved in signal transduction, which has raised the interest in FA-dependent signaling pathways. Here, we report that the c-Jun N-terminal kinase (JNK) fails to phosphorylate in response to UV radiation and treatment with mitomycin C in FA lymphoblast cells derived from type A patients (FA-A). Furthermore, defective kinase activity seems to be specific for JNK, because extracellular signal-regulated kinase (ERK) responded to the proper stimuli in FA-A cells. We also demonstrate that the early growth-response factor-1 (Egr-1), a JNK downstream target gene that is normally induced by genotoxic stress, is not upregulated in UV-treated FA-A cells. Moreover, FA-A cells are more sensitive to apoptosis than control lymphoblasts. Both JNK and Egr-1 may be part of a pathway triggered by FA proteins, because functional correction of FA-A cells by gene transfer restores, at least in part, JNK activation and Egr-1 expression after UV exposure. Together, our data suggest that activation of JNK and expression of Egr-1 gene in B lymphoblasts mediate a cellular response to genotoxic agents that may be induced by FA proteins.
Pipaon
Carlos
C
Unidad de Genetica Molecular, Hospital Universitario Marques de Valdecilla, Santander, Spain.
Casado
Jose Antonio
JA
Bueren
Juan Antonio
JA
Fernandez-Luna
Jose Luis
JL
D001402:B-Lymphocytes / Q000378:metabolism / Q000528:radiation effects; D001483:Base Sequence; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation / Q000528:radiation effects; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism*; D052217:Fanconi Anemia Complementation Group A Protein; D005816:Genetic Complementation Test; D006801:Humans; D017874:Immediate-Early Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014466:Ultraviolet Rays
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D017874:Immediate-Early Proteins; D011506:Proteins; D014157:Transcription Factors