A pathway in quiescent cells that controls p27^Kip1 stability, subcellular localization, and tumor suppression

Abstract

We have created two knock-in mouse models to study the mechanisms that regulate p27 in normal cells and cause misregulation of p27 in tumors: p27 S10A , in which Ser10 is mutated to Ala; and p27 CK − , in which point mutations abrogate the ability of p27 to bind cyclins and CDKs. These two mutant alleles identify steps in a pathway that controls the proteasomal degradation of p27 uniquely in quiescent cells: Dephosphorylation of p27 on Ser10 inhibits p27 nuclear export and promotes its assembly into cyclin-CDK complexes, which is, in turn, necessary for p27 turnover. We further show that Ras-dependent lung tumorigenesis is associated with increased phosphorylation on Ser10 and cytoplasmic mislocalization of p27. Indeed, we find that p27 S10A is refractory to Ras-induced cytoplasmic translocation and that p27 S10A mice are tumor resistant. Thus, phosphorylation of p27 on Ser10 is an important event in the regulation of the tumor suppressor function of p27.[Keywords: p27 Kip1 ; cyclin; CDK; tumor suppressor; tumorigenesis; Ras; lung cancer] Supplemental material is available at http://www.genesdev.org.

Formation of E-Cadherin/β-Catenin–based Adherens Junctions in Hepatocytes Requires Serine-10 in p27(Kip1)

“…Because p27 has been demonstrated to display also noncell cycle-related functions in the cytoplasm that depend on its phosphorylation at Ser10 (McAllister et al, 2003;Besson et al, 2006), we next examined the phosphorylation of p27 on Ser10 in response to oncostatin M. As shown in Figure 1, A and B, the 4-h treatment of HepG2 cells with oncostatin M results in a ϳ1.5-fold increase in the phosphorylation status of p27 at Ser-10. Pretreatment of the cells with PD98059 (50 M), which effectively inhibits the activation of p42/44 MAPK by MAPK kinase in response to oncostatin M (Wojtal et al, 2007), prevents the oncostatin M-stimulated increase in p27-Ser10 phosphorylation ( Figure 1A).…”

“…In addition, p27S10A knockin mice, which display a normal body size, do not reveal a clear organismal phenotype (Besson et al, 2006;Kotake et al, 2005). To examine adherens junctions in hepatocytes from p27S10A knockin mice, which express the mutant protein under the control of the endogenous promotor of p27, liver coupes from 4-mo-old p27S10A knockin mice and control wild-type mice (Besson et al, 2006) were immunolabeled for E-cadherin and ␤-catenin and counterstained with hematoxylin. As shown in Figure 11, B and D, E-cadherin was largely retained intracellularly in hepatocytes from p27S10A knockin mice, in contrast to their more prominent localization at the surface of hepatocytes from normal mice (Figure 11, A and C).…”

“…p27(Kip1) controls cell cycle progression (Polyak et al, 1994) and, interestingly, displays additional non-cell cycle-related functions including differentiation (Deschênes et al, 2001), apoptosis (Drexler, 2003), and migration (McAllister et al, 2003;Besson et al, 2004;Denicourt et al, 2007). The main phosphorylation site in p27(Kip1), Ser10, has been proposed to be an important determinant for non-cell cycle-related cytoplasmic functions of p27(Kip1) (see McAllister et al, 2003;Besson et al, 2006). In this study, we have investigated the involvement of p27(Kip1) and its Ser10 phosphorylation site in (OSM-stimulated) cell-cell adhesion.…”

Un nouveau rôle de p27KIP1dans la mitose ?

“…De plus, la surexpression du liaison aux complexes cycline/CDK, Skp2 est incapable de s'y lier, ce qui empêche son ubiquitinylation et sa dégradation. Par conséquent, le niveau de p27 CK-est anormalement élevé dans les phases S/G2/M du cycle cellulaire [5].…”

“…De plus, l'expression de p27 CK-est capable d'induire la multinucléation de cellules de chacune de ces protéines dans la cytocinèse et, plus particulièrement, dans l'interaction entre p27 et citron-K ou RhoA. ◊ A new function for p27 KIP1 [5] et du cervelet [6]. Dans les neurones, le gène UBE3A est soumis à empreinte : il n'est normalement exprimé qu'à partir de l'allèle maternel sur le chromosome 15, tandis que l'allèle d'origine paternelle reste virtuellement silencieux.…”