Degradation of p27 at the G0-G1 Transition Mediated by a Skp2-independent Ubiquitination Pathway

CRM1/Ran-Mediated Nuclear Export of p27Kip1Involves a Nuclear Export Signal and Links p27 Export and Proteolysis

“…Recent data using T187A knock-in and Skp2 -/-mice suggest that more than one mechanism regulates p27 proteolysis, and that p27 proteolysis is T187 independent in early G1 (Hara et al, 2001;Malek et al, 2001). We observed that the interaction between p27 and CRM1 begins at a time in the cell cycle when both Skp2 protein levels and cyclin E-Cdk2 activities are low.…”

“…Both our own data and that of others indicate that S10 phosphorylation is important for CRM1 binding and is required for p27 export (Rodier et al, 2001;Ishida et al, 2002). Binding of nucleoporins, such as Nup50, may facilitate translocation of p27 to the cytoplasm (Guan et al, 2000), where it is ubiquitylated and degraded (Hara et al, 2001). This early phase of exportlinked p27 proteolysis appears to precede Skp2 up-regulation and cyclin E-cdk2 activation and is independent of phosphorylation on T187 by cyclin E-Cdk 2, consistent with other recent reports (Hara et al, 2001;Malek et al, 2001;Ishida et al, 2002).…”

“…T187 phosphorylation allows recognition of p27 by its SCF-type E3 ligase, comprised of Skp1, Cul1, and the F-box protein, Skp2 and Roc1 and the Cks1 cofactor Ohta et al, 1999;Sutterluty et al, 1999;Tsvetkov et al, 1999;Ganoth et al, 2001;Spruck et al, 2001). Recent evidence suggests that p27 proteolysis is regulated by at least two distinct mechanisms, with mitogenic signaling conditioning p27 for degradation in early G1 in a manner independent of T187 phosphorylation (Hara et al, 2001;Malek et al, 2001), whereas Skp2-dependent cyclin E-Cdk 2-mediated degradation occurs in S phase after T187 phosphorylation (Malek et al, 2001). …”

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

“…Indeed, the limited potential of p27 in predicting the clinical outcome has previously been realized in a subset of DLBCL and most mantle cell lymphomas [12]. These findings suggested involvement of a Skp2-independent proteolytic mechanism for down-regulation of p27 [27], possibly leading to a distinct potential in predicting prognosis between Skp2 and p27. Recently, it has been demonstrated that the cytoplasmic p27 was an important indicator for poor patient prognosis because this dislocation of p27 impaired p27-mediated G1 arrest of the cell cycle [28].…”

Deregulated degradation of the cdk inhibitor p27 and malignant transformation

“…As detailed in the text, p27 and Skp2 function upstream of cyclin E. Due to the nature of these proteins, the G1/S transition is regulated by the alternating activity of proto-oncogenes and tumor suppressors to keep in check the events leading to cell proliferation. event is still dependent on Skp2 [27], the other one favors a model in which p27 is degraded in G1 and perhaps in G0 in a Skp2-independent manner [28]. However, these investigations do not clarify whether the rate of p27 degradation in early-mid G1 is increased compared to G0 or whether translational mechanisms are responsible for p27 reduction in early-mid G1 [29].…”