However, these observations were disputed by a more recent report by Oksvold et al., arguing that UV exposure did not induce dimerization, tyrosine phosphorylation, or activation of EGF-R ( 31). Involvement of c-Src, Ha-Ras, and Raf-1 in the cellular response to UV exposure has also been suggested by experiments using tyrosine kinase inhibitors and dominant negative mutants ( 6). Cross-linking of these cell surface proteins induced by UV might be mediated by reactive oxygen intermediates ( 16). In particular, it has been proposed by several groups that UV irradiation induces ligand-independent activation of receptors for epidermal growth factor (EGF), tumor necrosis factor, and interleukin-1 that triggers the cytoplasmic signaling cascade leading to activation of JNK ( 16, 33, 38, 39). However, it appears to involve signal relay of a MAP kinase signaling cascade from membrane-proximal events rather than a response to DNA damage in the nucleus ( 33). ![]() The molecular mechanism for activation of JNK by UV irradiation is not fully understood. It is also possible that the three members of JNK, JNK1, JNK2, and JNK3, have overlapping yet distinct functions in various cell types ( 18). Apparently, whether JNK activates a proapoptotic or an antiapoptotic pathway might depend on the cellular context or the degree to which JNK is activated ( 23). Characterization of fibroblast cells defective for c-Jun or c-Fos expression even suggested a protective role of JNK against cell apoptosis ( 30, 41). For example, suppression of the JNK pathway does not block Fas-induced apoptosis in Jurkat T cells ( 26). However, JNK activation is sometimes not associated with cell apoptosis ( 18). JNK is activated during cellular responses to external stress, such as UV irradiation, heat shock, and inflammatory cytokines ( 41), and this group of kinases has been implicated in the activation of caspases and initiation of apoptotic process in a variety of cell types ( 40, 41). ![]() JNK, also known as stress-activated protein kinase, is a group of mitogen-activated protein (MAP) kinases that include the extracellular signal regulated kinase (ERK) and p38 MAP kinase ( 32). Exposure of cells to UV also rapidly induces the activation of c-Jun NH 2-terminal kinases (JNK) that phosphorylate and activate transcription factors, including c-Jun and ATF2 ( 18). UV irradiation can have multiple effects on mammalian cells, such as DNA damage through formation of pyrimidine dimers and 6-4 photoproducts and induced expression of genes that are involved in DNA repair, cell growth, and apoptosis ( 8, 12). The human population will possibly face the exposure of increasing doses of short-wavelength UV irradiation due to progressive destruction of the ozone layer by industrial pollution, with the direct outcome of increasing rates of skin cancer. In aggregate, these observations identify a new function of Gab1 in the response of mammalian cells to UV light. Genetic and pharmaceutical analyses suggest the involvement of c-Met and the Src family tyrosine kinases in mediating UV-induced Gab1 phosphorylation as well as JNK activation. Gab1 was constitutively complexed with JNK and became tyrosine phosphorylated in UV-irradiated cells. Consistently, Gab1 −/− cells displayed reduced caspase 3 induction and apoptotic cell death in response to UV irradiation. Gab1-deficient mouse fibroblast cells were defective in induction of JNK activity by UV exposure or heat shock, and this defect was rescued by reintroduction of Gab1 into Gab1 −/− cells. We show here an essential role of a multisubstrate adapter, Gab1, in this signaling cascade. However, the molecular mechanism for JNK activation by UV exposure is not fully understood. ![]() Exposure of mammalian cells to UV irradiation leads to activation of the c-Jun NH 2-terminal protein kinase (JNK) pathway, which is associated with cell apoptosis.
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