Molecular mechanism for the actions of inhibitory proteins on stress activated protein kinase pathway

Abstract

The stress-activated protein kinases (SAPKs), which are identical to the c-Jun N- terminal kinases (JNKs), are serine/threonine-specific protein kinase and belong to the mammalian mitogen-activated protein kinase (MAPK) family. SAPK/JNK can be activated in response to a variety of cellular stresses, including DNA damage, heat shock, or tumor necrosis factor-α Although physiological function of SAPK/JNK is not understood completely, one of the major functions of SAPK/JNK appears to phosphorylate and activate c-Jun and other transcription factors including ATF-2 and Elk-1 in cellular response to a variety of stresses. The phosphorylation of the transcription factors by SAPK/JNK is thought to be important in stress-activated signaling cascades. In the present study, SAPK was stimulated after exposure of cells to ultraviolet (UV) irradiation. In order to investigate a possible regulatory role of p21 in stress-activated signaling pathways, I examined the action of p21 on the SAPK pathway activated by UV irradiation. p21WAF1/CIP1/Sdi1 is a DNA damage- inducible cell-cycle inhibitory protein. In this study, p21WAF1/CIP1/Sdi1, acts as an inhibitor of the SAPK group among mammalian MAP kinases. Physical association of SAPK and p21WAF1/CIP1/Sdi1 was confirmed by yeast two hybrid in vivo assay. This highlights a new biochemical activity of p21, which may provide the first evidence for a nonenzymatic inhibitory protein for SAPK. I suggest that p21 , by inhibiting SAPK, may have a role in the regulation of SAPK signaling cascades that are activated by cellular stresses such as DNA damage. The Rb protein, another cell cycle regulatory protein,is the product of the retinoblastoma susceptibility gene and loss of Rb function is detected in many types of human cancers. Rb plays important roles in the regulation of cell proliferation, differentiation, senescence, and apoptotic cell death. The pleiotropic functions of Rb are attributed to its ability to interact with a variety of ...