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Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate.

Gamat M, Malinowski RL, Parkhurst LJ, Steinke LM, Marker PC - PLoS ONE (2015)

Bottom Line: Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens.DFMO also significantly decreased the expression of developmental regulatory gene Notch1.Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI, United States of America.

ABSTRACT
The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

No MeSH data available.


Related in: MedlinePlus

mRNA levels of polyamine biosynthetic and catabolic enzymes in the cultured UGS.The mRNA levels of biosynthetic enzymes Arg1 (A), Odc1 (B), Amd1 (C), Srm (D) and Sms (E) did not change in response to treatment with testosterone or T+DFMO. Similarly, the regulatory enzymes Oaz1 (F), Sat1 (G) and Paox (H) were also unchanged in response to testosterone or T+DFMO.
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pone.0139522.g005: mRNA levels of polyamine biosynthetic and catabolic enzymes in the cultured UGS.The mRNA levels of biosynthetic enzymes Arg1 (A), Odc1 (B), Amd1 (C), Srm (D) and Sms (E) did not change in response to treatment with testosterone or T+DFMO. Similarly, the regulatory enzymes Oaz1 (F), Sat1 (G) and Paox (H) were also unchanged in response to testosterone or T+DFMO.

Mentions: In the previous section, we showed that inhibiting polyamine biosynthesis reduces prostatic budding. We then asked whether the presence of androgens and/or inhibiting polyamine biosynthesis in the UGS affected the transcription of polyamine biosynthetic or catabolic enzymes. We cultured the UGS for six days in no steroid media (NS), testosterone supplemented media (T) or testosterone and DFMO supplemented media (T+DFMO), then snap froze the tissue for downstream gene analysis. Culturing the UGS in testosterone did not induce mRNA transcription of biosynthetic enzymes arginase (Arg1, Fig 5A), ornithine decarboxylase (Odc1, Fig 5B), S-adenosylmethionine decarboxylase (Amd1, Fig 5C), spermidine synthase (Srm, Fig 5D) and spermine synthase (Sms, Fig 5E). Similiarly, culturing the UGS in T+DFMO did not alter mRNA expression levels of any of the polyamine biosynthetic enzymes examined (Fig 5A–5E).


Ornithine Decarboxylase Activity Is Required for Prostatic Budding in the Developing Mouse Prostate.

Gamat M, Malinowski RL, Parkhurst LJ, Steinke LM, Marker PC - PLoS ONE (2015)

mRNA levels of polyamine biosynthetic and catabolic enzymes in the cultured UGS.The mRNA levels of biosynthetic enzymes Arg1 (A), Odc1 (B), Amd1 (C), Srm (D) and Sms (E) did not change in response to treatment with testosterone or T+DFMO. Similarly, the regulatory enzymes Oaz1 (F), Sat1 (G) and Paox (H) were also unchanged in response to testosterone or T+DFMO.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4591331&req=5

pone.0139522.g005: mRNA levels of polyamine biosynthetic and catabolic enzymes in the cultured UGS.The mRNA levels of biosynthetic enzymes Arg1 (A), Odc1 (B), Amd1 (C), Srm (D) and Sms (E) did not change in response to treatment with testosterone or T+DFMO. Similarly, the regulatory enzymes Oaz1 (F), Sat1 (G) and Paox (H) were also unchanged in response to testosterone or T+DFMO.
Mentions: In the previous section, we showed that inhibiting polyamine biosynthesis reduces prostatic budding. We then asked whether the presence of androgens and/or inhibiting polyamine biosynthesis in the UGS affected the transcription of polyamine biosynthetic or catabolic enzymes. We cultured the UGS for six days in no steroid media (NS), testosterone supplemented media (T) or testosterone and DFMO supplemented media (T+DFMO), then snap froze the tissue for downstream gene analysis. Culturing the UGS in testosterone did not induce mRNA transcription of biosynthetic enzymes arginase (Arg1, Fig 5A), ornithine decarboxylase (Odc1, Fig 5B), S-adenosylmethionine decarboxylase (Amd1, Fig 5C), spermidine synthase (Srm, Fig 5D) and spermine synthase (Sms, Fig 5E). Similiarly, culturing the UGS in T+DFMO did not alter mRNA expression levels of any of the polyamine biosynthetic enzymes examined (Fig 5A–5E).

Bottom Line: Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens.DFMO also significantly decreased the expression of developmental regulatory gene Notch1.Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI, United States of America.

ABSTRACT
The prostate is a male accessory sex gland that produces secretions in seminal fluid to facilitate fertilization. Prostate secretory function is dependent on androgens, although the mechanism by which androgens exert their effects is still unclear. Polyamines are small cationic molecules that play pivotal roles in DNA transcription, translation and gene regulation. The rate-limiting enzyme in polyamine biosynthesis is ornithine decarboxylase, which is encoded by the gene Odc1. Ornithine decarboxylase mRNA decreases in the prostate upon castration and increases upon administration of androgens. Furthermore, testosterone administered to castrated male mice restores prostate secretory activity, whereas administering testosterone and the ornithine decarboxylase inhibitor D,L-α-difluromethylornithine (DFMO) to castrated males does not restore prostate secretory activity, suggesting that polyamines are required for androgens to exert their effects. To date, no one has examined polyamines in prostate development, which is also androgen dependent. In this study, we showed that ornithine decarboxylase protein was expressed in the epithelium of the ventral, dorsolateral and anterior lobes of the adult mouse prostate. Ornithine decarboxylase protein was also expressed in the urogenital sinus (UGS) epithelium of the male and female embryo prior to prostate development, and expression continued in prostatic epithelial buds as they emerged from the UGS. Inhibiting ornithine decarboxylase using DFMO in UGS organ culture blocked the induction of prostatic buds by androgens, and significantly decreased expression of key prostate transcription factor, Nkx3.1, by androgens. DFMO also significantly decreased the expression of developmental regulatory gene Notch1. Other genes implicated in prostatic development including Sox9, Wif1 and Srd5a2 were unaffected by DFMO. Together these results indicate that Odc1 and polyamines are required for androgens to exert their effect in mediating prostatic bud induction, and are required for the expression of a subset of prostatic developmental regulatory genes including Notch1 and Nkx3.1.

No MeSH data available.


Related in: MedlinePlus