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TGF-{beta} maintains dormancy of prostatic stem cells in the proximal region of ducts.

Salm SN, Burger PE, Coetzee S, Goto K, Moscatelli D, Wilson EL - J. Cell Biol. (2005)

Bottom Line: This conclusion is supported by the observations showing that high levels of TGF-beta 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.A physiological TGF-beta 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-beta, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
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)-beta than the distal ductal region and that under physiological conditions androgens and TGF-beta are crucial overall regulators of prostatic tissue homeostasis. This conclusion is supported by the observations showing that high levels of TGF-beta 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-beta signaling gradient, leading to an increase in TGF-beta signaling in the unprotected distal region (low Bcl-2 expression). This reversal of TGF-beta-mediated signaling accompanies apoptosis of cells in the distal region and gland involution after androgen withdrawal. A physiological TGF-beta 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-beta, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

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TβRI expression is regulated by androgens in proximal and distal cells. TβRI was detected using RT-PCR (A) and Western blot (B) in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates.
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fig4: TβRI expression is regulated by androgens in proximal and distal cells. TβRI was detected using RT-PCR (A) and Western blot (B) in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates.

Mentions: Prostates were removed from mice at time 0 (intact prostate) and 1, 3, 8, and 14 d after castration. After 14 d of involution, some mice were given androgen and prostates were removed 1, 3, 8, and 14 d later. The proximal and distal regions were examined by RT-PCR (Fig. 4 A) and Western blot (Fig. 4 B) analysis to determine whether androgen withdrawal affected the expression of TβRI and II. TβRI mRNA and protein levels increased both proximally and distally after castration and continued to increase until day 8, and then leveled off. After 8 d of involution, receptor mRNA and protein levels in the proximal region were 1.5-fold (P < 0.01) and 10-fold (P < 0.01) higher, respectively, than those of the androgen-replete prostate. Similar increases in mRNA (1.5-fold; P < 0.01) and protein (15-fold; P < 0.001) levels were noted in the distal region at this time (Fig. 4, A and B). After the administration of androgens, the levels of receptor mRNA and protein decreased both proximally and distally, although after 8 d of androgen supplementation, protein levels of TβRI remained four- (proximal) or sevenfold (distal) higher than the levels observed in the androgen-replete prostate (Fig. 4, A and B). Similar results were observed with TβRII (unpublished data). Thus, TGF-β receptor expression is diminished by androgens both proximally and distally. The increase in receptor expression in the distal region after castration may result in an increase in sensitivity to TGF-β, leading to apoptosis and the involution of this region of the gland.


TGF-{beta} maintains dormancy of prostatic stem cells in the proximal region of ducts.

Salm SN, Burger PE, Coetzee S, Goto K, Moscatelli D, Wilson EL - J. Cell Biol. (2005)

TβRI expression is regulated by androgens in proximal and distal cells. TβRI was detected using RT-PCR (A) and Western blot (B) in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates.
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Related In: Results  -  Collection

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fig4: TβRI expression is regulated by androgens in proximal and distal cells. TβRI was detected using RT-PCR (A) and Western blot (B) in the intact prostate (T0), the prostate 1 (D1-A), 3 (D3-A), and 8 d (D8-A) after castration and after 1 (D1+A), 3 (D3+A), and 8 d (D8+A) of androgen administration to animals with involuted prostates.
Mentions: Prostates were removed from mice at time 0 (intact prostate) and 1, 3, 8, and 14 d after castration. After 14 d of involution, some mice were given androgen and prostates were removed 1, 3, 8, and 14 d later. The proximal and distal regions were examined by RT-PCR (Fig. 4 A) and Western blot (Fig. 4 B) analysis to determine whether androgen withdrawal affected the expression of TβRI and II. TβRI mRNA and protein levels increased both proximally and distally after castration and continued to increase until day 8, and then leveled off. After 8 d of involution, receptor mRNA and protein levels in the proximal region were 1.5-fold (P < 0.01) and 10-fold (P < 0.01) higher, respectively, than those of the androgen-replete prostate. Similar increases in mRNA (1.5-fold; P < 0.01) and protein (15-fold; P < 0.001) levels were noted in the distal region at this time (Fig. 4, A and B). After the administration of androgens, the levels of receptor mRNA and protein decreased both proximally and distally, although after 8 d of androgen supplementation, protein levels of TβRI remained four- (proximal) or sevenfold (distal) higher than the levels observed in the androgen-replete prostate (Fig. 4, A and B). Similar results were observed with TβRII (unpublished data). Thus, TGF-β receptor expression is diminished by androgens both proximally and distally. The increase in receptor expression in the distal region after castration may result in an increase in sensitivity to TGF-β, leading to apoptosis and the involution of this region of the gland.

Bottom Line: This conclusion is supported by the observations showing that high levels of TGF-beta 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.A physiological TGF-beta 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-beta, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT
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)-beta than the distal ductal region and that under physiological conditions androgens and TGF-beta are crucial overall regulators of prostatic tissue homeostasis. This conclusion is supported by the observations showing that high levels of TGF-beta 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-beta signaling gradient, leading to an increase in TGF-beta signaling in the unprotected distal region (low Bcl-2 expression). This reversal of TGF-beta-mediated signaling accompanies apoptosis of cells in the distal region and gland involution after androgen withdrawal. A physiological TGF-beta 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-beta, these findings may have important implications for the deregulation of the stem cell compartment in the etiology of proliferative prostatic diseases.

Show MeSH
Related in: MedlinePlus