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PIN1, the cell cycle and cancer

Nature Reviews Cancer volume 7, pages 381–388 (2007)Cite this article

Key Points

  • PIN1 is a member of the evolutionarily conserved peptidyl-prolyl isomerase family of proteins, which encompasses the cyclophilins, FK506-binding proteins and the parvulins.

  • PIN1 binds to and alters the conformation of phosphoproteins by catalysing the rapid cis to trans isomerization of proline amide bonds contained within the target proteins.

  • The isomerization of proteins by PIN1 results in an alteration of protein structure and/or function, which is often coupled to a change in protein stabilization.

  • PIN1 was originally identified as a cell cycle protein (mitotic). Subsequently, many cell-cycle regulatory proteins (G1/S, M and checkpoint) were identified as PIN1 binding partners. Given its ability to regulate these important proteins, PIN1 is suggested to act a molecular 'timer' of the cell cycle.

  • PIN1 is overexpressed in some human cancers in correlation with cyclin D1 and β-catenin overexpression. Such correlations have led to the idea that PIN1 might be tumour promoting.

  • The loss of PIN1 also promotes the stabilization of two important oncogenes, MYC and cyclin E. The germline deletion of Pin1 promotes rapid genomic instability in mouse embryo fibroblasts in a p53-dependent manner that encourages more aggressive Ras-induced transformation of these PIN1-null cells. Therefore, it has been suggested that PIN1 might act as a tumour suppressor.

  • The contradictory experimental observations regarding the function of PIN1 in cancer remain enigmatic, but raise the possibility that PIN1 can either function as a tumour promoter or conditional tumour suppressor.

Abstract

PIN1 is a peptidyl-prolyl isomerase that can alter the conformation of phosphoproteins and so affect protein function and/or stability. PIN1 regulates a number of proteins important for cell-cycle progression and, based on gain- and loss-of-function studies, is presumed to operate as a molecular timer of this important process. Therefore, it seems logical that alterations in the level of PIN1 can influence hyperproliferative diseases such as cancer. However, the precise role of PIN1 in cancer remains controversial.

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Figure 1: PIN1 catalyses the cis–trans isomerization of prolyl bonds.
Figure 2: Functional targets of PIN1.
Figure 3: PIN1 promotes cyclin E degradation mediated by the FBXW7 E3 ligase.

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Acknowledgements

Research cited from the author's laboratory was funded by grants from the US National Institutes of Health.

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  1. Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, 4th floor BRB II/III 421 Curie Boulevard, Philadelphia, 19104–6160, Pennsylvania, USA

    Elizabeth S. Yeh

  2. Department of Pharmacology and Cancer Biology, C238 Levine Science Research Center, PO BOX 3813, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Anthony R. Means

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Yeh, E., Means, A. PIN1, the cell cycle and cancer. Nat Rev Cancer 7, 381–388 (2007). https://doi.org/10.1038/nrc2107

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