Stimulation of c-Jun/AP-1-Activity by the Cell Cycle Inhibitor p57Kip2

Abstract

p57 is a member of the Cip/Kip family of cell cycle inhibitors which restrict the eukaryotic cell cycle by binding to and inhibiting cyclin/CDK complexes. They are considered as tumor suppressors and inactivating genomic mutations of p57 are associated with human overgrowth disorders. Increasing evidence suggests that p57 controls additional cellular processes beyond cell cycle control such as apoptosis, cell migration or transcription. Here we report that p57 can stimulate AP-1 promotor activity. While transactivation by c-Jun is strongly activated by p57, it did not enhance c-Fos induced transcription. This indicates that c-Jun is the target of p57 in the canonical AP-1 heterodimeric transcription factor. We could detect endogenous p57/c-Jun containing complexes in cells by co-immunoprecipitation. The strong stimulation of c-Jun activity is not the consequence of activating phosphorylation in the transactivation domain (TAD) of c-Jun, but rather due to negative interference with c-Jun repressors and positive interference with c-Jun activators. In contrast to full-length p57, the amino- and carboxy-terminal domains of p57 are insufficient for a significant activation of c-Jun induced transcription. When expressed in presence of full length p57, the p57 C-terminus abrogated and the N-terminus enhanced c-Jun activation. This indicates that the C-terminus may bind and sequester a putative activator of c-Jun, whereas the N-terminus may sequester a c-Jun repressor. Interestingly, the p57 aminoterminus is sufficient for binding to the two c-Jun repressors HDAC1 and HDAC3. These data are consistent with a model of c-Jun activation where p57 is a part of large nuclear remodeling/transcription complexes. p57 might stimulate transcription by inhibiting transcription repressor proteins like HDACs via its N-terminus and/or attracting transcription activators through its C-terminus. These data suggest that in addition to its role as a CDK inhibitor and tumor suppressor, p57 may also exert tumor promoting functions by activation of the proto-oncoprotein c-Jun.

The cyclin‐dependent kinase inhibitor p27Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

“…Phosphorylation of p27 Kip1 at T157 and T198 in PI3K‐hyperactivated cancers has been shown to drive p27 Kip1 binding to Janus kinase 2 (JAK2) and separately, it was demonstrated that this phosphorylated form of p27 Kip1 can bind and transcriptionally co‐activate c‐Jun. Interestingly, the related p57 kip2 has also been shown to exert transcriptional co‐regulatory activity [59], including the regulation of c‐Jun [60].…”

p57Kip2 acts as a transcriptional corepressor to regulate intestinal stem cell fate and proliferation

“…p57 may also control transcription by regulating RNA Polymerase II C-terminal domain (CTD) phosphorylation in an E2F1-dependent manner [54]. More recently, p57 was found to promote c-Jun and FHL2 mediated transcription by competing with HDAC1 and HDAC3 for binding to these transcription factors, thereby relieving their inhibition by HDACs [55, 56]. Interestingly, while the N-terminus of p57 acted as a transactivator, presumably by competing with HDACs, the C-terminus of p57 repressed c-Jun activity, suggesting a complex regulation that may depend on the binding partners of p57 and/or on posttranslational modifications [55].…”

Based on Network Pharmacology Tools to Investigate the Mechanism of Tripterygium wilfordii Against IgA Nephropathy

“…COX-derived prostanoids appear to be involved in the pathogenesis of diabetic nephropathy (41), and a recent study regarded prostaglandins as potential targets for the treatment of polycystic kidney disease (42). JUN is a positive regulator of cell proliferation which promotes cell proliferation by accelerating G1-S cell cycle progression (43)(44)(45). It could bind with FOS to form AP-1 (Activator protein-1) early transcription response factor and mediate many biological functions (46,47).…”