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.
Highlights
Cell cycle involves a series of sequential events and is divided into several phases including protein synthesis in G1 phase, DNA synthesis in S phase, cell growth in G2 phase, chromosome segregation in mitosis and cell separation in cytokinesis
PIN1 directly binds to the phosphorylated Thr286-Pro motif of cyclin D1 to increase cyclin D1 stability and nuclear accumulation. These findings suggest that PIN1 over-expression increases cyclin D1 expression to promote cell cycle progression through the release of E2F transcription factors from phosphorylated retinoblastoma protein (Rb)
We showed that PIN1 expression stabilizes p27, and reduces its binding affinity with cyclin E-CDK2, thereby impairing its CDK2-inhibitory activity
Summary
Cell cycle involves a series of sequential events and is divided into several phases including protein synthesis in G1 phase, DNA synthesis in S phase, cell growth in G2 phase, chromosome segregation in mitosis and cell separation in cytokinesis. PIN1 binds the phosphorylated Thr246Pro motif of β-catenin to prevent cytoplasmic translocation and protein degradation of β-catenin (Ryo et al, 2001) This results in the stabilization and transcriptional activation of β-catenin, which in turn enhances cyclin D1 expression. Despite its effect on decreasing cyclin E and increasing p27 levels, over-expression of PIN1 has been shown to promote cell proliferation in different cell types To explain this apparent paradoxical phenomenon, a recent study by our group has demonstrated that PIN1 relieves CDK2 inhibition by regulating the CDK2-inhibitory activity of p27. Two mitotic protein kinases, Wee and Myt, have been found to induce the phosphorylation of CDK1 subunit at Thr and Tyr, resulting in inhibition of cyclin B-CDK1 activity and preventing cell mitosis prematurely. ATO directly binds to the PIN1 catalytic domain by a non-covalent mechanism and induces PIN1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
