Downregulation of the KIP family members p27^KIP1 and p57^KIP2 by SKP2 and the role of methylation in p57^KIP2 inactivation in nonsmall cell lung cancer

Abstract

Knowing the status of molecules involved in cell cycle control in cancer is vital for therapeutic approaches aiming at their restoration. The p27 KIP1 and p57 KIP2 cyclin-dependent kinase inhibitors are nodal factors controlling normal cell cycle. Their expression in normal lung raises the question whether they have a mutual exclusive or redundant role in nonsmall cell lung cancer (NSCLC). A comparative comprehensive analysis was performed in a series of 70 NSCLCs. The majority of cases showed significantly reduced expression of both members compared to normal counterparts. Low KIP protein levels correlated with increased proliferation, which seems to be histological subtype preponderant. At mechanistic level, degradation by SKP2 was demonstrated, in vivo and in vitro, by siRNA-methodology, to be the most important downregulating mechanism of both KIPs in NSCLC. Decreased p57 ), suggested that inhibition of the SKP2-degradation mechanism restores p27 KIP1 and p57 KIP2 expression. Double siRNA treatments demonstrated that each KIP is independently capable of restraining cell growth. An additional demethylation step is required for complete reconstitution of p57 KIP2 expression in NSCLC. ' 2006 Wiley-Liss, Inc.

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

“…Third, translocation of p57 Kip2 from the nucleus to the mitochondria was detected in live HeLa cells within 20 min after STS exposure. In fact, cytoplasmic localization for p57 Kip2 has been reported in non-small-cell lung carcinoma 20 and esophageal squamous cell carcinoma. 33 In addition, during osteoblast differentiation, cytoplasmic p57 Kip2 was found to inhibit LIM-kinase 1, a kinase involved in actin p57 Kip2 promotes apoptotic cell death P Vlachos et al filament dynamics, by translocating and sequestering it in the nucleus.…”

“…7 Taken together, these observations suggest that that p57 Kip2 exerts tissue-specific effects during development. Interestingly during adulthood, it has also been reported that p57 Kip2 expression is reduced in various tumors, [8][9][10][11][12][20][21][22][23][24] suggesting a possible function for this protein in tumorigenesis. Importantly, decreased p57 Kip2 expression may provide an important prognostic implication for patients with ovarian, hepatocellular and colorectal cancers, and acute lymphoblastic leukemia.…”

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.…”

“…In 2006, Pateras and colleagues (102) investigated p57 Kip2 content in 70 NSCLCs and identified a protein decrease (which was particularly evident in the nuclear compartment) in 89% of the cases. Functional studies showed that the reduction was due to methylation, allelic imprinting, and increased degradation (102). (133) analyzed 82 breast cancer samples for CDKN1C alterations.…”

The Cdk inhibitor p57Kip2 controls LIM-kinase 1 activity and regulates actin cytoskeleton dynamics

“…, most probably because of its Cdk inhibitory function, is frequently considered as a nuclear protein; however, cytoplasmic expression of this protein has been demonstrated in various tissue, tumors and derived cell lines (www.proteinatlas.org; Barbe et al, 2008;Nan et al, 2005;Matsumoto et al, 2000;Pateras et al, 2006;Bozdogan et al, 2008;Joseph et al, 2009). In fact, as for the other members of the family, p21…”