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Peptidyl-prolyl cis–trans isomerase Pin1 in ageing, cancer and Alzheimer disease

  • Tae Ho Lee (a1), Lucia Pastorino (a1) and Kun Ping Lu (a1)
Abstract

Phosphorylation of proteins on serine or threonine residues preceding proline is a key signalling mechanism in diverse physiological and pathological processes. Pin1 (peptidyl-prolyl cis–trans isomerase) is the only enzyme known that can isomerise specific Ser/Thr-Pro peptide bonds after phosphorylation and regulate their conformational changes with high efficiency. These Pin1-catalysed conformational changes can have profound effects on phosphorylation signalling by regulating a spectrum of target activities. Interestingly, Pin1 deregulation is implicated in a number of diseases, notably ageing and age-related diseases, including cancer and Alzheimer disease. Pin1 is overexpressed in most human cancers; it activates numerous oncogenes or growth enhancers and also inactivates a large number of tumour suppressors or growth inhibitors. By contrast, ablation of Pin1 prevents cancer, but eventually leads to premature ageing and neurodegeneration. Consistent with its neuroprotective role, Pin1 has been shown to be inactivated in neurons of patients with Alzheimer disease. Therefore, Pin1-mediated phosphorylation-dependent prolyl isomerisation represents a unique signalling mechanism that has a pivotal role in the development of human diseases, and might offer an attractive new diagnostic and therapeutic target.

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Corresponding author
*Corresponding author: Kun Ping Lu, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, CLS 0408, Boston, MA 02215, USA. E-mail: klu@bidmc.harvard.edu
References
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168Hashemzadeh-Bonehi, L. et al. (2006) Pin1 protein associates with neuronal lipofuscin: potential consequences in age-related neurodegeneration. Experimental Neurology 199, 328-338
169Fujimori, F. et al. (1999) Mice lacking Pin1 develop normally, but are defective in entering cell cycle from G(0) arrest. Biochemical and Biophysical Research Communications 265, 658-663
170Toledo, F. et al. (2007) Mouse mutants reveal that putative protein interaction sites in the p53 proline-rich domain are dispensable for tumor suppression. Molecular and Cellular Biology 27, 1425-1432
171Rapoport, M. et al. (2002) Tau is essential to beta-amyloid-induced neurotoxicity. Proceedings of the National Academy of Sciences of the United States of America 99, 6364-6369
172Kuramochi, J. et al. (2006) High Pin1 expression is associated with tumor progression in colorectal cancer. Journal of Surgical Oncology 94, 155-160
173Fukuchi, M. et al. (2006) Prolyl isomerase Pin1 expression predicts prognosis in patients with esophageal squamous cell carcinoma and correlates with cyclinD1 expression. International Journal of Oncology 29, 329-334
174Leung, K.W. et al. (2009) Pin1 overexpression is associated with poor differentiation and survival in oral squamous cell carcinoma. Oncology Reports 21, 1097-1104
175Tan, X. et al. (2010) Pin1 expression contributes to lung cancer: prognosis and carcinogenesis. Cancer Biology and Therapy 9, 111-119
176Ryo, A. et al. (2002) Pin1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. Molecular and Cellular Biology 22, 5281-5295
177Ryo, A. et al. (2005) Stable suppression of tumorigenicity by Pin1-targeted RNA interference in prostate cancer. Clinical Cancer Research 11, 7523-7531
178Hennig, L. et al. (1998) Selective inactivation of parvulin-like peptidyl-prolyl cis/trans isomerases by juglone. Biochemistry 37, 5953-5960
179Uchida, T. et al. (2003) Pin1 and Par14 peptidyl prolyl isomerase inhibitors block cell proliferation. Chemistry and Biology 10, 15-24
180Wildemann, D. et al. (2006) Nanomolar inhibitors of the peptidyl prolyl cis/trans isomerase Pin1 from combinatorial peptide libraries. Journal of Medicinal Chemistry 49, 2147-2150
181Potter, A.J. et al. (2010) Structure-guided design of alpha-amino acid-derived Pin1 inhibitors. Bioorganic and Medicinal Chemistry Letters 20, 586-590
182Guo, C. et al. (2009) Structure-based design of novel human Pin1 inhibitors (I). Bioorganic and Medicinal Chemistry Letters 19, 5613-5616
183Zhao, S. and Etzkorn, F.A. (2007) A phosphorylated prodrug for the inhibition of Pin1. Bioorganic and Medicinal Chemistry Letters 17, 6615-6618
184Xu, G.G. and Etzkorn, F.A. (2009) Pin1 as an anticancer drug target. Drug News and Perspectives 22, 399-407
185Wildemann, D. et al. (2007) An essential role for Pin1 in Xenopus laevis embryonic development revealed by specific inhibitors. Biological Chemistry 388, 1103-1111
186Zhang, Y. et al. (2007) Structural basis for high-affinity peptide inhibition of human Pin1. ACS Chemical Biology 2, 320-328
187Liu, T. et al. (2010) Membrane permeable cyclic peptidyl inhibitors against human Peptidylprolyl Isomerase Pin1. Journal of Medicinal Chemistry 53, 2494-2501
188Wulf, G. et al. (2003) The prolyl isomerase Pin1 in breast development and cancer. Breast Cancer Research 5, 76-82

The following papers describe in detail the mechanisms of prolyl cis–trans isomerisation that are not discussed in this review. Other diseases involving Pin1 deregulation are also reviewed.

Behrens, M.I. et al. (2009) A common biological mechanism in cancer and Alzheimer's disease? Current Alzheimer Research 6, 196-204
Lu, K.P. and Zhou, X.Z. (2007) The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nature Reviews. Molecular Cell Biology 8, 904-916
Lu, K.P. et al. (2007) Prolyl cis-trans isomerization as a molecular timer. Nature Chemical Biology 3, 619-629
Wulf, G. et al. (2005) Phosphorylation-specific prolyl isomerization: is there an underlying theme? Nature Cell Biology 7, 435-441
The UCSD-Nature Signaling Gateway Molecule Pages provide general information about Pin1, its regulation and interacting proteins:http://www.signaling-gateway.org/molecule/
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Expert Reviews in Molecular Medicine
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