p57KIP2 Modulates Stress-activated Signaling by Inhibiting c-Jun NH2-terminal Kinase/Stress-activated Protein Kinase

Abstract

p57KIP2 , a member of the Cip/Kip family of enzymes that inhibit several cyclin-dependent kinases, plays a role in many biological events including cell proliferation, differentiation, apoptosis, tumorigenesis and developmental changes. The human p57 KIP2 gene is located in chromosome 11p15.5, a region implicated in sporadic cancers and Beckwith-Wiedemann syndrome. We here report that p57 KIP2 physically interacts with and inhibits c-Jun NH 2 -terminal kinase/stress-activated protein kinase (JNK/SAPK). The carboxyl-terminal QT domain of p57 KIP2 is crucial for the inhibition of JNK/ SAPK. Overexpressed p57 KIP2 also suppressed UV-and MEKK1-induced apoptotic cell death. p57 KIP2 expression during C2C12 myoblast differentiation resulted in repression of the JNK activity stimulated by UV light. Furthermore, UV-stimulated JNK1 activity was higher in mouse embryonic fibroblasts derived from p57 ؊/؊ mice than in the cells from wild-type mice. Taken together, these findings suggest that p57 KIP2 modulates stress-activated signaling by functioning as an endogenous inhibitor of JNK/SAPK.

The cell cycle inhibitor p57Kip2 promotes cell death via the mitochondrial apoptotic pathway

“…In fact, it has previously been reported that p57 Kip2 expression inhibits green tea polyphenol-induced apoptosis in oral carcinoma cells 29 or suppresses UV-and MEKK1-induced apoptotic cell death in HEK-293 cells. 30 However, to our surprise, in our hands, p57 Kip2 expression did not prevent UV-, STS-and CP-induced apoptotic cell death in HEK-293 cells. The cell type-specific effect may be related to differences in the stability of p57 Kip2 within cells or the number of cell survival pathways that are active in a particular cell type.…”

p57Kip2 and Cancer: Time for a Critical Appraisal

“…In some experimental models, p57 Kip2 showed antiapoptotic activity, whereas other studies revealed no correlation between p57 Kip2 and apoptosis (47,102). Therefore, p57 Kip2 relevance in apoptosis is probably confined to specific conditions and cell types.…”

“…This allows p57 Kip2 to interact with PCNA, although with a much lower affinity compared with p21 Cip1 , and in turn block processive DNA synthesis (46). In addition, the p57 Kip2 QT domain interacts with and inhibits the kinase activity of c-Jun NH2-terminal kinase/stress-activated protein kinase [JNK/SAPK (47,48)]. Of interest, p21 Cip1 is also able to bind and suppress JNK/SAPK activity via its amino-terminal domain.…”

Common and specific roles of the related CDK inhibitors p27 and p57 revealed by a knock-in mouse model

“…These differences are possibly attributable to differences in the spatiotemporal patterns of p27 and p57 expression (18), to structural features of p57 not shared by p27 (Fig. 1A), or to differences in the interactions of the 2 CKIs with proteins other than CDKs (19)(20)(21)(22)(23)(24)(25)(26)(27). However, given that previous studies have not evaluated the intrinsic differences between p27 and p57 under physiological conditions, the differences in their in vivo roles have remained unclear.…”