Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14). The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67). For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas. p53 was detected more frequently in large-cell MCL (l-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19). In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were p27 positive. Reverse transcription–polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P = .001), the loss of p27 (P = .002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P = .002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials. (Blood. 2000;95:619-626)

PI3K/Akt signaling regulates p27kip1 expression via Skp2 in PC3 and DU145 prostate cancer cells, but is not a major factor in p27kip1 regulation in LNCaP and PC346 cells

“…However, a relationship between PTEN deficiency and decreased p27 kip1 expression in clinical prostate cancer is not clear [56][57][58]. Skp2 overexpression has been described in many tumors [33,35,59]. In the study of Yang and coworkers [32], an inverse correlation between Skp2 and p27 kip1 was reported in prostate tumors.…”

Prognostic significance of the F‐box protein Skp2 expression in diffuse large B‐cell lymphoma

“…Dysregulation in expressions of CDK inhibitors, such as p15 and p16, has also been shown to be involved in lymphomagenesis [21]. Tracing these trends, recent studies have focused on the involvement of the universal CDK inhibitor p27 in lymphomagenesis [12,13,22,23], because p27 is known to be an amount-dependent tumor-suppressive protein [6]. Indeed, a reduced intracellular concentration of p27 protein in cancer cells has been shown to correlate with poor prognosis [6,8], and the loss of p27 allele in mice increased the sensitivity of these animals to carcinogenic agents [24].…”

Development of the Proteasome Inhibitor PS-341

“…While the exact mechanism for this differential susceptibility is not fully understood, proteasome inhibition may reverse some of the changes that permit proliferation and suppress apoptosis in malignant cells. For example, the cyclin-dependent kinase inhibitor p27 is degraded by the proteasome [18], and the decreased protein levels observed in some malignant cells are achieved by upregulation of proteasome-mediated p27 degradation [22]. When simian-virus-40-transformed fibroblasts are treated with a proteasome inhibitor, p27 levels increase substantially and apoptosis ensues [23].…”