JNK

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JNK

Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the MAP kinase family. MAP kinases act by phosphorylating various substrates including transcription factors. These in turn regulate expression of specific sets of genes and thus can mediate a specific genetic response to the stimulus. . Members of the JNK subgroup of MAP kinases are activated in response to diverse extracellular stimuli, including UV irradiation, proinflammatory cytokines and certain mitogens. The JNKs phosphorylate specific sites on the amino terminal trans-activation domain of transcription factor c-Jun, an important component of transcriptional activator AP-1. Phosphorylation of these sites stimulates the ability of c-Jun to activate transcription of specific target genes. In addition to c-Jun, the JNKs phosphorylate and activate several other transcription factors, most of which can contribute to AP-1 activity. JNK is also activated by growth factors, as well as by other stimuli including TNFa, IL-1, osmotic stress, and various stimuli that activate heterotrimeric G protein coupled receptors. JNK is activated by both Ha-Ras dependent pathways in response to growth factors such as EGF, and by Ha-Ras independent pathways in response to the cytokines TNFa and IL-1. While some stimuli operate through Rac or Cdc42Hs, other may operate by RacrCdc42Hs independent mechanisms.

The JNK protein kinases are activated by phosphorylation on Thr and Tyr by MKK4 (also known as SEK1) and MKK7. Once activated, JNK phosphorylates a number of targets. It was originally identified however, based on its ability to phosphorylate specific sites on the amino terminal activation domain of c-Jun. Phosphorylation of these sites dramatically stimulates c-Jun’s activity as a transcription factor. c-Jun, encoded by the c-jun proto-oncogene, is a sequence specific transcription factor whose function has been implicated in various cellular events ranging from cell proliferation and differentiation to neoplastic transformation. Although a variety of functions have been attributed to the JNKs, it is difficult to generalize, since their functions are also likely to vary depending on a variety of cellular and environmental conditions. As JNK is activated by a variety of cellular stresses, it has been proposed to serve as a major ’on’ switch for programmed cell death. TNFa is a potent activator of the JNK pathway, and can induce apoptosis in some tumor cells. JNK has been proposed to be a major mediator of apoptosis in response to TNFa.

Recently it has been found that Hsp72 mediates suppression of a stress-activated protein kinase, JNK, an early component of stress-induced apoptotic signalling pathway. This finding provides the basis for the anti-apoptotic activity of Hsp72. These observations can explain increased stress sensitivity of aged cells in which compromised inducibility of Hsp72 leads to a loss of control of JNK activation by stresses and subsequently to a higher rate of apoptotic death.