Published online 27 June 2005. doi:10.1083/jcb.200412015
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 170, Number 1, 81-90
TGF-ß maintains dormancy of prostatic stem cells in the proximal region of ducts
Sarah N. Salm1,4,
Patricia E. Burger5,
Sandra Coetzee1,
Ken Goto1,6,
David Moscatelli1,2, and
E. Lynette Wilson1,2,3,5
1 Department of Cell Biology, New York University School of Medicine, New York, NY 10016
2 Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016
3 Department of Urology, New York University School of Medicine, New York, NY 10016
4 Department of Science, Borough of Manhattan Community College, New York, NY 10007
5 Division of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town Medical School, Cape Town 7925, South Africa
6 Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Correspondence to E. Lynette Wilson: wilsoe01{at}endeavor.med.nyu.edu
We have previously shown that prostatic stem cells are located in the proximal region of mouse prostatic ducts. Here, we show that this region responds differently to transforming growth factor (TGF)-ß than the distal ductal region and that under physiological conditions androgens and TGF-ß are crucial overall regulators of prostatic tissue homeostasis. This conclusion is supported by the observations showing that high levels of TGF-ß signaling are present in the quiescent proximal region of ducts in an androgen-replete animal and that cells in this region overexpress Bcl-2, which protects them from apoptosis. Moreover, androgen ablation reverses the proximal-distal TGF-ß signaling gradient, leading to an increase in TGF-ß signaling in the unprotected distal region (low Bcl-2 expression). This reversal of TGF-ß–mediated signaling accompanies apoptosis of cells in the distal region and gland involution after androgen withdrawal. A physiological TGF-ß signaling gradient (high proximally and low distally) and its functional correlates are restored after androgen replenishment. In addition to highlighting the regulatory role of androgens and TGF-ß, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.
Abbreviations used in this paper: BMP, bone morphogenetic protein; BPH, benign prostatic hyperplasia; IGF-1, insulin-like growth factor 1; LTBP-1, latent TGF-ß binding protein; MFI, mean fluorescence intensity; pSMAD, phosphorylated SMAD; SCF, stem cell factor; TMLC, TGF-ß–responsive mink lung cells.
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