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Science 287 (5458): 1644-1647

Copyright © 2000 by the American Association for the Advancement of Science

Requirement of the Prolyl Isomerase Pin1 for the Replication Checkpoint

Katharine E. Winkler, Katherine I. Swenson, Sally Kornbluth, Anthony R. Means *

The peptidyl-prolyl isomerase Pin1 has been implicated in regulating cell cycle progression. Pin1 was found to be required for the DNA replication checkpoint in Xenopus laevis. Egg extracts depleted of Pin1 inappropriately transited from the G2 to the M phase of the cell cycle in the presence of the DNA replication inhibitor aphidicolin. This defect in replication checkpoint function was reversed after the addition of recombinant wild-type Pin1, but not an isomerase-inactive mutant, to the depleted extract. Premature mitotic entry in the absence of Pin1 was accompanied by hyperphosphorylation of Cdc25, activation of Cdc2/cyclin B, and generation of epitopes recognized by the mitotic phosphoprotein antibody, MPM-2. Therefore, Pin1 appears to be required for the checkpoint delaying the onset of mitosis in response to incomplete replication.

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813, Durham, NC 27710, USA.
*   To whom correspondence should be addressed. E-mail: means001{at}

Differential Regulation of Cellular Senescence and Differentiation by Prolyl Isomerase Pin1 in Cardiac Progenitor Cells.
H. Toko, N. Hariharan, M. H. Konstandin, L. Ormachea, M. McGregor, N. A. Gude, B. Sundararaman, E. Joyo, A. Y. Joyo, B. Collins, et al. (2014)
J. Biol. Chem. 289, 5348-5356
   Abstract »    Full Text »    PDF »
Pin1 acts as a negative regulator of the G2/M transition by interacting with the Aurora-A-Bora complex.
Y.-C. Lee, J. Que, Y.-C. Chen, J.-T. Lin, Y.-C. Liou, P.-C. Liao, Y.-P. Liu, K.-H. Lee, L.-C. Lin, M. Hsiao, et al. (2013)
J. Cell Sci. 126, 4862-4872
   Abstract »    Full Text »    PDF »
Pin1 Regulates the Dynamics of c-Myc DNA Binding To Facilitate Target Gene Regulation and Oncogenesis.
A. S. Farrell, C. Pelz, X. Wang, C. J. Daniel, Z. Wang, Y. Su, M. Janghorban, X. Zhang, C. Morgan, S. Impey, et al. (2013)
Mol. Cell. Biol. 33, 2930-2949
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Pin1 Interacts with the Epstein-Barr Virus DNA Polymerase Catalytic Subunit and Regulates Viral DNA Replication.
Y. Narita, T. Murata, A. Ryo, D. Kawashima, A. Sugimoto, T. Kanda, H. Kimura, and T. Tsurumi (2013)
J. Virol. 87, 2120-2127
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Peptidyl-Prolyl Isomerase Pin1 Is a Cellular Factor Required for Hepatitis C Virus Propagation.
Y.-S. Lim, H. T. L. Tran, S.-J. Park, S.-A. Yim, and S. B. Hwang (2011)
J. Virol. 85, 8777-8788
   Abstract »    Full Text »    PDF »
Peptidyl-prolyl Cis/Trans Isomerase NIMA-interacting 1 Associates with Insulin Receptor Substrate-1 and Enhances Insulin Actions and Adipogenesis.
Y. Nakatsu, H. Sakoda, A. Kushiyama, J. Zhang, H. Ono, M. Fujishiro, T. Kikuchi, T. Fukushima, M. Yoneda, H. Ohno, et al. (2011)
J. Biol. Chem. 286, 20812-20822
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Pin1 Associates with and Induces Translocation of CRTC2 to the Cytosol, Thereby Suppressing cAMP-responsive Element Transcriptional Activity.
Y. Nakatsu, H. Sakoda, A. Kushiyama, H. Ono, M. Fujishiro, N. Horike, M. Yoneda, H. Ohno, Y. Tsuchiya, H. Kamata, et al. (2010)
J. Biol. Chem. 285, 33018-33027
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Cytosolic Aryl Sulfotransferase 4A1 Interacts with the Peptidyl Prolyl Cis-Trans Isomerase Pin1.
D. J. Mitchell and R. F. Minchin (2009)
Mol. Pharmacol. 76, 388-395
   Abstract »    Full Text »    PDF »
Human Immunodeficiency Virus Type 1 Replication and Regulation of APOBEC3G by Peptidyl Prolyl Isomerase Pin1.
K. Watashi, M. Khan, V. R. K. Yedavalli, M. L. Yeung, K. Strebel, and K.-T. Jeang (2008)
J. Virol. 82, 9928-9936
   Abstract »    Full Text »    PDF »
Degradation of the Tumor Suppressor PML by Pin1 Contributes to the Cancer Phenotype of Breast Cancer MDA-MB-231 Cells.
E. L. Reineke, M. Lam, Q. Liu, Y. Liu, K. J. Stanya, K.-S. Chang, A. R. Means, and H.-Y. Kao (2008)
Mol. Cell. Biol. 28, 997-1006
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The Prolyl Isomerase Pin1 Affects Che-1 Stability in Response to Apoptotic DNA Damage.
F. De Nicola, T. Bruno, S. Iezzi, M. Di Padova, A. Floridi, C. Passananti, G. Del Sal, and M. Fanciulli (2007)
J. Biol. Chem. 282, 19685-19691
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Post-phosphorylation prolyl isomerisation of gephyrin represents a mechanism to modulate glycine receptors function.
M. Moretto Zita, I. Marchionni, E. Bottos, M. Righi, G. Del Sal, E. Cherubini, and P. Zacchi (2007)
EMBO J. 26, 1761-1771
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Pin1 stabilizes Emi1 during G2 phase by preventing its association with SCF{beta}trcp.
C. Bernis, S. Vigneron, A. Burgess, J.-C. Labbe, D. Fesquet, A. Castro, and T. Lorca (2007)
EMBO Rep. 8, 91-98
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Regulation of Bruton Tyrosine Kinase by the Peptidylprolyl Isomerase Pin1.
L. Yu, A. J. Mohamed, L. Vargas, A. Berglof, G. Finn, K. P. Lu, and C. I. E. Smith (2006)
J. Biol. Chem. 281, 18201-18207
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The Protein Phosphatase 2A Phosphatase Activator Is a Novel Peptidyl-Prolyl cis/trans-Isomerase.
J. Jordens, V. Janssens, S. Longin, I. Stevens, E. Martens, G. Bultynck, Y. Engelborghs, E. Lescrinier, E. Waelkens, J. Goris, et al. (2006)
J. Biol. Chem. 281, 6349-6357
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Pin1 Regulates Centrosome Duplication, and Its Overexpression Induces Centrosome Amplification, Chromosome Instability, and Oncogenesis.
F. Suizu, A. Ryo, G. Wulf, J. Lim, and K. P. Lu (2006)
Mol. Cell. Biol. 26, 1463-1479
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The Loss of PIN1 Deregulates Cyclin E and Sensitizes Mouse Embryo Fibroblasts to Genomic Instability.
E. S. Yeh, B. O. Lew, and A. R. Means (2006)
J. Biol. Chem. 281, 241-251
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Peptidyl-Prolyl Isomerase 1 (Pin1) Serves as a Coactivator of Steroid Receptor by Regulating the Activity of Phosphorylated Steroid Receptor Coactivator 3 (SRC-3/AIB1).
P. Yi, R.-C. Wu, J. Sandquist, J. Wong, S. Y. Tsai, M.-J. Tsai, A. R. Means, and B. W. O'Malley (2005)
Mol. Cell. Biol. 25, 9687-9699
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The Ess1 prolyl isomerase is dispensable for growth but required for virulence in Cryptococcus neoformans.
P. Ren, A. Rossettini, V. Chaturvedi, and S. D. Hanes (2005)
Microbiology 151, 1593-1605
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PINA Is Essential for Growth and Positively Influences NIMA Function in Aspergillus nidulans.
J. D. Joseph, S. N. Daigle, and A. R. Means (2004)
J. Biol. Chem. 279, 32373-32384
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Spermatogonial Depletion in Adult Pin1-Deficient Mice.
F. W. Atchison and A. R. Means (2003)
Biol Reprod 69, 1989-1997
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The Prolyl Isomerase Pin1 Is a Novel Prognostic Marker in Human Prostate Cancer.
G. Ayala, D. Wang, G. Wulf, A. Frolov, R. Li, J. Sowadski, T. M. Wheeler, K. P. Lu, and L. Bao (2003)
Cancer Res. 63, 6244-6251
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Pin1 regulates the timing of mammalian primordial germ cell proliferation.
F. W. Atchison, B. Capel, and A. R. Means (2003)
Development 130, 3579-3586
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Peptide Binding Induces Large Scale Changes in Inter-domain Mobility in Human Pin1.
D. M. Jacobs, K. Saxena, M. Vogtherr, P. Bernado, M. Pons, and K. M. Fiebig (2003)
J. Biol. Chem. 278, 26174-26182
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Structural Analysis of the Mitotic Regulator hPin1 in Solution: INSIGHTS INTO DOMAIN ARCHITECTURE AND SUBSTRATE BINDING.
E. Bayer, S. Goettsch, J. W. Mueller, B. Griewel, E. Guiberman, L. M. Mayr, and P. Bayer (2003)
J. Biol. Chem. 278, 26183-26193
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Prolyl isomerase Pin1: a catalyst for oncogenesis and a potential therapeutic target in cancer.
A. Ryo, Y.-C. Liou, K. P. Lu, and G. Wulf (2003)
J. Cell Sci. 116, 773-783
   Abstract »    Full Text »    PDF »
Phosphorylation of the Cyclin B1 Cytoplasmic Retention Sequence by Mitogen-Activated Protein Kinase and Plx.
S. Walsh, S. S. Margolis, and S. Kornbluth (2003)
Mol. Cancer Res. 1, 280-289
   Abstract »    Full Text »    PDF »
A New Identity for MLK3 as an NIMA-related, Cell Cycle-regulated Kinase That Is Localized near Centrosomes and Influences Microtubule Organization.
K. I. Swenson, K. E. Winkler, and A. R. Means (2003)
Mol. Biol. Cell 14, 156-172
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Role of Pin1 in the Regulation of p53 Stability and p21 Transactivation, and Cell Cycle Checkpoints in Response to DNA Damage.
G. M. Wulf, Y.-C. Liou, A. Ryo, S. W. Lee, and K. P. Lu (2002)
J. Biol. Chem. 277, 47976-47979
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M. M. Messenger, R. B. Saulnier, A. D. Gilchrist, P. Diamond, G. J. Gorbsky, and D. W. Litchfield (2002)
J. Biol. Chem. 277, 23054-23064
   Abstract »    Full Text »    PDF »
Peptidyl-prolyl isomerases: a new twist to transcription.
P. E. Shaw (2002)
EMBO Rep. 3, 521-526
   Abstract »    Full Text »    PDF »
The Ess1 Prolyl Isomerase Is Required for Growth and Morphogenetic Switching in Candida albicans.
G. Devasahayam, V. Chaturvedi, and S. D. Hanes (2002)
Genetics 160, 37-48
   Abstract »    Full Text »    PDF »
Isolation and characterization of the Pin1/Ess1p homologue in Schizosaccharomyces pombe.
H.-k. Huang, S. L. Forsburg, U. P. John, M. J. O'Connell, and T. Hunter (2001)
J. Cell Sci. 114, 3779-3788
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Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1.
G. M. Wulf, A. Ryo, G. G. Wulf, S. W. Lee, T. Niu, V. Petkova, and K. P. Lu (2001)
EMBO J. 20, 3459-3472
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S and G2 Phase Roles for Cdk2 Revealed by Inducible Expression of a Dominant-Negative Mutant in Human Cells.
B. Hu, J. Mitra, S. van den Heuvel, and G. H. Enders (2001)
Mol. Cell. Biol. 21, 2755-2766
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The Ess1 prolyl isomerase is linked to chromatin remodeling complexes and the general transcription machinery.
X. Wu, C. B. Wilcox, G. Devasahayam, R. L. Hackett, M. Arevalo-Rodriguez, M. E. Cardenas, J. Heitman, and S. D. Hanes (2000)
EMBO J. 19, 3727-3738
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Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3-Rpd3 histone deacetylase.
M. Arevalo-Rodriguez, M. E. Cardenas, X. Wu, S. D. Hanes, and J. Heitman (2000)
EMBO J. 19, 3739-3749
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Phosphorylation-dependent Proline Isomerization Catalyzed by Pin1 Is Essential for Tumor Cell Survival and Entry into Mitosis.
J. F. Rippmann, S. Hobbie, C. Daiber, B. Guilliard, M. Bauer, J. Birk, H. Nar, P. Garin-Chesa, W. J. Rettig, and A. Schnapp (2000)
Cell Growth Differ. 11, 409-416
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Critical Role of WW Domain Phosphorylation in Regulating Phosphoserine Binding Activity and Pin1 Function.
P.-J. Lu, X. Z. Zhou, Y.-C. Liou, J. P. Noel, and K. P. Lu (2002)
J. Biol. Chem. 277, 2381-2384
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p13SUC1 and the WW Domain of PIN1 Bind to the Same Phosphothreonine-Proline Epitope.
I. Landrieu, B. Odaert, J.-M. Wieruszeski, H. Drobecq, P. Rousselot-Pailley, D. Inze, and G. Lippens (2001)
J. Biol. Chem. 276, 1434-1438
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Functional Replacement of the Essential ESS1 in Yeast by the Plant Parvulin DlPar13.
M. Metzner, G. Stoller, K. P. Rucknagel, K. P. Lu, G. Fischer, M. Luckner, and G. Kullertz (2001)
J. Biol. Chem. 276, 13524-13529
   Abstract »    Full Text »    PDF »
Functional Conservation of Phosphorylation-specific Prolyl Isomerases in Plants.
J.-L. Yao, O. Kops, P.-J. Lu, and K. P. Lu (2001)
J. Biol. Chem. 276, 13517-13523
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1H NMR Study on the Binding of Pin1 Trp-Trp Domain with Phosphothreonine Peptides.
R. Wintjens, J.-M. Wieruszeski, H. Drobecq, P. Rousselot-Pailley, L. Buee, G. Lippens, and I. Landrieu (2001)
J. Biol. Chem. 276, 25150-25156
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