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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.


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