PIN1 in Cell Cycle Control and Cancer

Abstract

Cell cycle progression is tightly controlled by many cell cycle-regulatory proteins that are in turn regulated by a family of cyclin-dependent kinases (CDKs) through protein phosphorylation. The peptidyl-prolyl cis/trans isomerase PIN1 provides a further post-phosphorylation modification and functional regulation of these CDK-phosphorylated proteins. PIN1 specifically binds the phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif of its target proteins and catalyzes the cis/trans isomerization on the pSer/Thr-Pro peptide bonds. Through this phosphorylation-dependent prolyl isomerization, PIN1 fine-tunes the functions of various cell cycle-regulatory proteins including retinoblastoma protein (Rb), cyclin D1, cyclin E, p27, Cdc25C, and Wee1. In this review, we discussed the essential roles of PIN1 in regulating cell cycle progression through modulating the functions of these cell cycle-regulatory proteins. Furthermore, the mechanisms underlying PIN1 overexpression in cancers were also explored. Finally, we examined and summarized the therapeutic potential of PIN1 inhibitors in cancer therapy.

Keywords: PIN1; cell cycle; checkpoint; isomerization; phosphorylation.

FIGURE 1

Essential role of PIN1 in regulation of cell cycle progression. Through phosphorylation-dependent prolyl isomerization, PIN1 regulates the functions of various cell cycle-regulatory proteins for cell cycle progression. To mediate the progression of G1 checkpoint, PIN1 activates cyclin D1-CDK4/6 through inactivation of retinoblastoma protein (Rb) and accumulation of cyclin D1 protein. PIN1 is able to promote G1-S phase transition by increasing CDK2 activity in spite of its paradoxical regulation of cyclin E and p27 levels. In G2 phase, PIN1 functions to regulate cyclin B-CDK1 activity through its modulation of the activity of Cdc25C protein phosphatase and Wee1 kinase. In addition, PIN1 regulates chromosome condensation and segregation through its interaction with topoisomerase (Topo) IIα and casein kinase (CK) 2, and separase, respectively. During cytokinesis, PIN1 alters the activities of centrosomal protein (CEP55) and septin 9 (SEPT9) that function to mediate midbody abscission. Consequently, PIN1 is required for cell cycle progression.

FIGURE 2

PIN1-mediated positive feedback loop for progression of G1 checkpoint. During G1 phase, PIN1 increases the binding of retinoblastoma protein (Rb) with cyclin D1-CDK4/6, resulting in inactivation of Rb and the release of E2F for the activation of PIN1 expression. Through PIN1-mediated isomerization, PIN1 enhances cyclin D1 expression by increasing the transcriptional activities of β-catenin, nuclear factor kappa B (NF-κB) and c-Jun. In addition, PIN1 also binds and increases the protein stability of cyclin D1, which in turn enhances its protein level. As a result, cyclin D1 binds and activates CDK4/6, leading to further inactivation of Rb for E2F dissociation.