The Molecular Biology of Progesterone Receptors: Why Are There Two Isoforms?
Progesterone is the reproductive and pregnancy hormone. Females without it are infertile. The major target tissues for progesterone are the ovary, uterus, mammary gland, and brain. Synthetic progestational agents are used for contraception and hormone replacement therapy and antiprogestins are in clinical trials for contraception and for the treatment of cancers and uterine disorders. The agonists and antagonists act at their target tissues by binding to progesterone receptors (PR) which consist of two isoforms: human B receptors (hPRB) are 933 amino acids in length, while human A receptors (hPRA) lack the N-terminal 164 amino acids, but are otherwise identical to B receptors. When A and B isoforms are present in equimolar amounts, they dimerize and bind DNA as three species: A/A and B/B homodimers, and A/B heterodimers. This heterogeneity has complicated the study of antiprogestins since each isoform and dimeric species has a unique ligand response profile that varies with the gene and cell in question (Horwitz 1992, and references therein). This chapter reviews recent work from our laboratory dealing with the two isoforms of human PR, focusing on antiprogestin actions in breast cancer cells. These studies have allowed us to pose, but not yet answer, the question in the title of this chapter.
KeywordsAndrogen Receptor Nuclear Localization Sequence Estrogen Response Element Thymidine Kinase Promoter Hormone Binding Domain
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