Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2

Abstract

Poor prognosis neuroblastoma (NB) tumors are marked by amplification and overexpression of N-myc. Retinoic acid (RA) decreases N-myc levels and induces cell cycle arrest in vitro and increases event-free survival in advanced stage NB patients. In this study, we investigated the mechanism(s) by which RA regulates cell cycle and how N-myc affects NB cell cycle progression. Constitutive N-myc overexpression stimulates increases in cyclin E-dependent kinase activity and decreases in p27 resulting in increased DNA synthesis.

Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins

“…In the present study, we demonstrate that, in LCLs, degradation of Cks1 protein was markedly inhibited by proteasome inhibitors, confirming that the Cks1 protein is regulated via the ubiquitin-proteasome pathway. However, unlike what was reported by Nakamura et al (2003) in neuroblastoma cells, we herein show that RA decreases Cks1 protein levels by increasing proteasome-dependent degradation of the protein. These results were confirmed in other neoplastic B cell lines, including those derived from patients with Burkitt's lymphoma or mantle cell lymphoma (data not shown), indicating that RA-induced downregulation of both p45 Skp2 and Cks1 is probably a general phenomenon in B lymphocytes.…”

“…Furthermore, Nakamura et al (2003) reported that RA induces cell cycle arrest in neuroblastoma cell lines by decreasing the levels of the N-myc mRNA and protein and stabilizing p27 Kip1 . In this cellular system, RA also induced a downregulation of p45 Skp2 that was, however, not associated with changes in Cks1 expression levels (Nakamura et al, 2003). In the present study, we demonstrate that, in LCLs, degradation of Cks1 protein was markedly inhibited by proteasome inhibitors, confirming that the Cks1 protein is regulated via the ubiquitin-proteasome pathway.…”

Key role for p27Kip1, retinoblastoma protein Rb, and MYCN in polyamine inhibitor-induced G1 cell cycle arrest in MYCN-amplified human neuroblastoma cells

“…It has previously been shown that DFMO blocks the expression of c-Myc (Tabib and Bachrach, 1994) and these findings are extended by our own results, which show strong downregulation of the c-Myc-related protein MYCN in response to DFMO or DFMO/SAM486A (Figure 5c). It has also been shown that MYCN can regulate p27 Kip1 in NB cells by targeting p27 Kip1 to the proteasome (Nakamura et al, 2003), and it is therefore possible that the observed increase in p27 Kip1 is in response to a decrease in MYCN. Figure 6 shows the possible involvement of polyamines in the regulation of p27 Kip1 , Rb, and MYCN in LAN-1 and NMB-7 cells based on our observations.…”

The Gap Junction-independent Tumor-suppressing Effect of Connexin 43

“…Transformation of PAX3-FKHR (the oncogenic form of the Pax3 transcription factor) elevated the level of Skp2 accompanied by reduced expression of p27 (26). In contrast, the tumor suppressor PTEN (27) and the anti-tumor agents retinoic acid (28,29), vitamin D analog (30), and troglitazone (31) caused decreases in Skp2 levels with concomitant increases of p27 proteins in tumor cells. Considering these studies and our observations, we propose that one of the explanations for Cx43 to function as a tumor-suppressing gene may be through targeting the proto-oncogene SKP2, and consequently increasing the level of the cell cycle controller p27.…”