Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle

doi:10.1016/S0960-0760(97)00119-2

The Journal of Steroid Biochemistry and Molecular Biology

Volume 63, Issues 4–6, November–December 1997, Pages 195-202

https://doi.org/10.1016/S0960-0760(97)00119-2 Get rights and content

Abstract

Recent studies suggest that the progesterone receptor isoforms (PR-A and PR-B) activate genes differentially and that PR-A may act as a repressor of PR-B function. Hence, the absolute and relative expression of the two isoforms will determine the response to progesterone. We have measured their relative expression in the uterus of cycling women who underwent endometrial biopsy. PR isoforms were identified on blots of SDS-PAGE gels by reaction with the AB-52 antibody after immunoprecipitation from endometrial extract. Both isoforms were highest in the peri-ovulatory phase, but levels of PR-A were always higher than those of PR-B. The ratio of PR-A to PR-B changed during the menstrual cycle. Between days 2 and 8, PR-B is almost undetectable and the A:B ratio is >10:1. From days 9 to 13, the ratio is about 5:1, and it is about 2:1 between days 14 and 16. Thereafter, PR-B dwindles rapidly and is virtually undetectable at the end of the cycle. In various hypoestrogenic environments, PR-B expression was reduced. However, exogenous estrogens in the follicular phase in the form of oral contraceptives, enhanced PR-B expression. These data support the possibility that progesterone acts through cycle-specific PR isoforms.

References (41)

M. Beato
Gene regulation by steroid hormones
Cell
(1989)
H. Loosfelt et al.
The rabbit progesterone receptor: evidence for a single steroid-binding subunit and characterization of receptor mRNA
J. Biol. Chem.
(1984)
R.L. Piekarz et al.
Progesterone regulates the murine multidrug resistance mdr lb gene
J. Biol. Chem.
(1993)
D. Chalbos et al.
Differential effect of forms A and B of the human progesterone receptor on estradiol-dependent transcription
J. Biol. Chem.
(1994)
D.P. McDonnell et al.
RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism
J. Biol. Chem.
(1994)
D.P. McDonnell et al.
The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity
J. Steroid Biochem. Molec. Biol.
(1994)
O.M. Conneely et al.
The A and B forms of a chicken progesterone receptor arise by alternate initiation of trnaslation of the unique mRNA
Biochem. Biophys. Res. Commun.
(1987)
P. Kastner et al.
Transient expression of human and chicken progesterone receptors does not support alternative transitional initiation from a single mRNA as the mechanism generating two receptor isoforms
J. Biol. Chem.
(1990)
W. Schneider et al.
Murine progesterone receptor exists predominantly as the 83-kilodalton ‘A’ form
J. Steroid Biochem. Molec. Biol.
(1991)
P.J.Q. van der Linden et al.
Expression of cadherins and integrins in human endometrium throughout the menstrual cycle
Fertil. and Steril.
(1995)

O. Jänne et al.

Oestrogen-induced progesterone receptor in human uterus

J. Steroid Biochem.

(1975)

K.B. Horwitz

Is a functional estrogen receptor always required for progesterone receptor induction in breast cancer?

J. Steroid Biochem.

(1981)

C.L. Clarke et al.

Progestin regulation of cellular proliferation

Endocrinol. Rev.

(1990)

M-J. Tsai et al.

Molecular mechanisms of action of steroid/thyroid receptor superfamily members

Ann. Rev. Biochem.

(1994)

K.B. Horwitz et al.

In situ photo linked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and translocation

Endocrinol.

(1983)

P.A. Boyd et al.

Seasonal changes in the molecular species and nuclear binding of the chicken oviduct progesterone receptor

Biochem.

(1979)

G. Shyamala et al.

Developmental regulation of murine mammary progesterone receptor gene expression

Endocrinol.

(1990)

L. Tung et al.

Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors

Mol. Endocrinol.

(1993)

W.L. Kraus et al.

Inhibitory cross-talk between steroid hormone receptors: differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist- and antagonist-occupied progestin receptors

Mol. Cell. Biol.

(1995)

E. Vegeto et al.

Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function

Mol. Endocrinol.

(1993)

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Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle

Abstract

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Steroid Biochem. Molec. Biol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Steroid Biochem. Molec. Biol.

Fertil. and Steril.

J. Steroid Biochem.

J. Steroid Biochem.

Progestin regulation of cellular proliferation

Endocrinol. Rev.

Molecular mechanisms of action of steroid/thyroid receptor superfamily members

Ann. Rev. Biochem.

In situ photo linked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and translocation

Endocrinol.

Seasonal changes in the molecular species and nuclear binding of the chicken oviduct progesterone receptor

Biochem.

Developmental regulation of murine mammary progesterone receptor gene expression

Endocrinol.

Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors

Mol. Endocrinol.

Inhibitory cross-talk between steroid hormone receptors: differential targeting of estrogen receptor in the repression of its transcriptional activity by agonist- and antagonist-occupied progestin receptors

Mol. Cell. Biol.

Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function

Mol. Endocrinol.