Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 99 (3): 1335-1340

Copyright © 2002 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes

Yih-Cherng Liou*,{dagger}, Akihide Ryo*,{dagger}, Han-Kuei Huang{ddagger}, Pei-Jung Lu*,§, Roderick Bronson, Fumihiro Fujimori||, Takafumi Uchida**, Tony Hunter{ddagger}, and Kun Ping Lu*,{ddagger}{ddagger}

*Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; {ddagger}Molecular and Cell Biology Laboratory, The Salk Institute, La Jolla, CA 92037; Tufts University School of Veterinary Medicine, Boston, MA 01536; ||Laboratory of Genome Biology, Department of Biological Science and Technology, Science University of Tokyo, Tokyo 162-8601, Japan; and **Department of Pathology, Tohoku University, Sendai 980-0077, Japan

Received for publication August 1, 2001.

Abstract: Phosphorylation of proteins on serine/threonine residues preceding proline is a key signaling mechanism. The conformation and function of a subset of these phosphorylated proteins is regulated by the prolyl isomerase Pin1 through isomerization of phosphorylated Ser/Thr-Pro bonds. Although young Pin1–/– mice have been previously shown to develop normally, we show here that they displayed a range of cell-proliferative abnormalities, including decreased body weight and testicular and retinal atrophies. Furthermore, in Pin1–/– adult females, the breast epithelial compartment failed to undergo the massive proliferative changes associated with pregnancy. Interestingly, many of these Pin1-deficient phenotypes such as retinal hypoplasia and mammary gland impairment are also the characteristic of cyclin D1-deficient mice. Cyclin D1 levels were significantly reduced in many tissues in Pin1-deficient mice, including retina and breast epithelial cells from pregnant mice. Moreover, Pin1 directly bound to cyclin D1 phosphorylated on Thr-286–Pro increased cyclin D1 in the nucleus and stabilized cyclin D1. These results indicate that Pin1 positively regulates cyclin D1 function at the transcriptional level, as demonstrated previously, and also through posttranslational stabilization, which together explain why Pin1 loss-of-function phenotypes in the mouse resemble cyclin D1-null phenotypes. Our results provide genetic evidence for an essential role of Pin1 in maintaining cell proliferation and regulating cyclin D1 function.

{dagger} Y.-C.L. and A.R. contributed equally to this work.

§ Present address: Institute of Biomedical Sciences, Kaohsivng 804, National Sun Yat-Sen University, Taiwan, People's Republic of China.

{ddagger}{ddagger} To whom reprint requests should be addressed. E-mail: klu{at}caregroup.harvard.edu.

Edited by Robert A. Weinberg, Whitehead Institute for Biomedical Research, Cambridge, MA, and approved December 6, 2001

This paper was submitted directly (Track II) to the PNAS office.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Regulation of Cardiac Hypertrophic Signaling by Prolyl Isomerase Pin1.
H. Toko, M. H. Konstandin, S. Doroudgar, L. Ormachea, E. Joyo, A. Y. Joyo, S. Din, N. A. Gude, B. Collins, M. Volkers, et al. (2013)
Circ. Res. 112, 1244-1252
   Abstract »    Full Text »    PDF »
Signaling Pathways that Control Cell Proliferation.
R. J. Duronio and Y. Xiong (2013)
Cold Spring Harb Perspect Biol 5, a008904
   Abstract »    Full Text »    PDF »
Regulation of Phosphatidylinositol-5-Phosphate Signaling by Pin1 Determines Sensitivity to Oxidative Stress.
W.-J. Keune, D. R. Jones, Y. Bultsma, L. Sommer, X. Z. Zhou, K. P. Lu, and N. Divecha (2012)
Science Signaling 5, ra86
   Abstract »    Full Text »    PDF »
Mixed-lineage kinase 3 phosphorylates prolyl-isomerase Pin1 to regulate its nuclear translocation and cellular function.
V. Rangasamy, R. Mishra, G. Sondarva, S. Das, T. H. Lee, J. C. Bakowska, G. Tzivion, J. S. Malter, B. Rana, K. P. Lu, et al. (2012)
PNAS 109, 8149-8154
   Abstract »    Full Text »    PDF »
Peptidyl-prolyl Isomerase Pin1 Controls Down-regulation of Conventional Protein Kinase C Isozymes.
H. Abrahamsen, A. K. O'Neill, N. Kannan, N. Kruse, S. S. Taylor, P. A. Jennings, and A. C. Newton (2012)
J. Biol. Chem. 287, 13262-13278
   Abstract »    Full Text »    PDF »
Loss of Heterochromatin Protein 1 Gamma Reduces the Number of Primordial Germ Cells via Impaired Cell Cycle Progression in Mice.
K. Abe, C. Naruse, T. Kato, T. Nishiuchi, M. Saitou, and M. Asano (2011)
Biol Reprod 85, 1013-1024
   Abstract »    Full Text »    PDF »
A Distinct Role for Pin1 in the Induction and Maintenance of Pluripotency.
M. Nishi, H. Akutsu, S. Masui, A. Kondo, Y. Nagashima, H. Kimura, K. Perrem, Y. Shigeri, M. Toyoda, A. Okayama, et al. (2011)
J. Biol. Chem. 286, 11593-11603
   Abstract »    Full Text »    PDF »
Phosphorylation stabilizes Nanog by promoting its interaction with Pin1.
M. Moretto-Zita, H. Jin, Z. Shen, T. Zhao, S. P. Briggs, and Y. Xu (2010)
PNAS 107, 13312-13317
   Abstract »    Full Text »    PDF »
Active Mek2 as a regulatory scaffold that promotes Pin1 binding to BPGAP1 to suppress BPGAP1-induced acute Erk activation and cell migration.
C. Q. Pan, Y.-c. Liou, and B. C. Low (2010)
J. Cell Sci. 123, 903-916
   Abstract »    Full Text »    PDF »
Pin1 Facilitates the Phosphorylation-Dependent Ubiquitination of SF-1 To Regulate Gonadotropin {beta}-Subunit Gene Transcription.
Z. Luo, A. Wijeweera, Y. Oh, Y.-C. Liou, and P. Melamed (2010)
Mol. Cell. Biol. 30, 745-763
   Abstract »    Full Text »    PDF »
G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression.
P. Penela, V. Rivas, A. Salcedo, and F. Mayor Jr. (2010)
PNAS 107, 1118-1123
   Abstract »    Full Text »    PDF »
A novel functional variant (-842G>C) in the PIN1 promoter contributes to decreased risk of squamous cell carcinoma of the head and neck by diminishing the promoter activity.
J. Lu, Z. Hu, S. Wei, L.-E Wang, Z. Liu, A. K. El-Naggar, E. M. Sturgis, and Q. Wei (2009)
Carcinogenesis 30, 1717-1721
   Abstract »    Full Text »    PDF »
Pin1 Catalyzes Conformational Changes of Thr-187 in p27Kip1 and Mediates Its Stability through a Polyubiquitination Process.
W. Zhou, Q. Yang, C. B. Low, B. C. Karthik, Y. Wang, A. Ryo, S. Q. Yao, D. Yang, and Y.-C. Liou (2009)
J. Biol. Chem. 284, 23980-23988
   Abstract »    Full Text »    PDF »
Expression of Pin1 mRNA in Non-Small-Cell Lung Cancer Patients.
Z. Ai, W. Zhang, W. Luo, L. Huang, and Y. Pan (2009)
Asian Cardiovascular and Thoracic Annals 17, 157-161
   Abstract »    Full Text »    PDF »
The prolyl isomerase Pin1 interacts with a ribosomal protein S6 kinase to enhance insulin-induced AP-1 activity and cellular transformation.
N. Y. Lee, H.-K. Choi, J.-H. Shim, K.-W. Kang, Z. Dong, and H. S. Choi (2009)
Carcinogenesis 30, 671-681
   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 »
Pin1-dependent Prolyl Isomerization Modulates the Stress-induced Phosphorylation of High Molecular Weight Neurofilament Protein.
P. Rudrabhatla, Y.-L. Zheng, N. D. Amin, S. Kesavapany, W. Albers, and H. C. Pant (2008)
J. Biol. Chem. 283, 26737-26747
   Abstract »    Full Text »    PDF »
Identification and Utility of FdmR1 as a Streptomyces Antibiotic Regulatory Protein Activator for Fredericamycin Production in Streptomyces griseus ATCC 49344 and Heterologous Hosts.
Y. Chen, E. Wendt-Pienkowski, and B. Shen (2008)
J. Bacteriol. 190, 5587-5596
   Abstract »    Full Text »    PDF »
Opposite Regulation of Oligodendrocyte Apoptosis by JNK3 and Pin1 after Spinal Cord Injury.
Q. M. Li, C. Tep, T. Y. Yune, X. Z. Zhou, T. Uchida, K. P. Lu, and S. O. Yoon (2007)
J. Neurosci. 27, 8395-8404
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
The Peptidyl-Prolyl Isomerase Pin1 Regulates Granulocyte-Macrophage Colony-Stimulating Factor mRNA Stability in T Lymphocytes.
S. Esnault, Z.-J. Shen, E. Whitesel, and J. S. Malter (2006)
J. Immunol. 177, 6999-7006
   Abstract »    Full Text »    PDF »
Loss of B-cell translocation gene-2 in estrogen receptor-positive breast carcinoma is associated with tumor grade and overexpression of cyclin d1 protein..
H. Kawakubo, E. Brachtel, T. Hayashida, G. Yeo, J. Kish, A. Muzikansky, P. D. Walden, and S. Maheswaran (2006)
Cancer Res. 66, 7075-7082
   Abstract »    Full Text »    PDF »
The Peptidylprolyl cis/trans-Isomerase Pin1 Modulates Stress-induced Dephosphorylation of Tau in Neurons: IMPLICATION IN A PATHOLOGICAL MECHANISM RELATED TO ALZHEIMER DISEASE.
M.-C. Galas, P. Dourlen, S. Begard, K. Ando, D. Blum, M. Hamdane, and L. Buee (2006)
J. Biol. Chem. 281, 19296-19304
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Stable Suppression of Tumorigenicity by Pin1-Targeted RNA Interference in Prostate Cancer.
A. Ryo, H. Uemura, H. Ishiguro, T. Saitoh, A. Yamaguchi, K. Perrem, Y. Kubota, K. P. Lu, and I. Aoki (2005)
Clin. Cancer Res. 11, 7523-7531
   Abstract »    Full Text »    PDF »
Oncogenic Signaling Pathways Activated in DMBA-Induced Mouse Mammary Tumors.
N. Currier, S. E. Solomon, E. G. Demicco, D. L. F. Chang, M. Farago, H. Ying, I. Dominguez, G. E. Sonenshein, R. D. Cardiff, Z.-X. J. Xiao, et al. (2005)
Toxicol Pathol 33, 726-737
   Abstract »    Full Text »    PDF »
Phosphorylation of Serine 147 of tis21/BTG2/pc3 by p-Erk1/2 Induces Pin-1 Binding in Cytoplasm and Cell Death.
J. W. Hong, M. S. Ryu, and I. K. Lim (2005)
J. Biol. Chem. 280, 21256-21263
   Abstract »    Full Text »    PDF »
Synthetic Lethality of Retinoblastoma Mutant Cells in the Drosophila Eye by Mutation of a Novel Peptidyl Prolyl Isomerase Gene.
K. A. Edgar, M. Belvin, A. L. Parks, K. Whittaker, M. B. Mahoney, M. Nicoll, C. C. Park, C. G. Winter, F. Chen, K. Lickteig, et al. (2005)
Genetics 170, 161-171
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Spermatogonial Depletion in Adult Pin1-Deficient Mice.
F. W. Atchison and A. R. Means (2003)
Biol Reprod 69, 1989-1997
   Abstract »    Full Text »    PDF »
Pin1 modulates the structure and function of human RNA polymerase II.
Y.-X. Xu, Y. Hirose, X. Z. Zhou, K. P. Lu, and J. L. Manley (2003)
Genes & Dev. 17, 2765-2776
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Pin1 regulates the timing of mammalian primordial germ cell proliferation.
F. W. Atchison, B. Capel, and A. R. Means (2003)
Development 130, 3579-3586
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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 »
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
   Abstract »    Full Text »    PDF »
PIN1 Is an E2F Target Gene Essential for Neu/Ras-Induced Transformation of Mammary Epithelial Cells.
A. Ryo, Y.-C. Liou, G. Wulf, M. Nakamura, S. W. Lee, and K. P. Lu (2002)
Mol. Cell. Biol. 22, 5281-5295
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882