Molecular biologic study on the growth inhibition of human endometrial glands.

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The growth of the glandular cells of the human endometrium is thought to be stimulated by estrogen, and inhibited by progestin. In the present study, to understand the progesterone-induced growth inhibition of the glandular cells of the human endometrium in a view of cell cycle regulatory machineries, following experiments ,were performed. (1) The immunohistochemical expression of cyclins and cyclin-dependent kinases (cdks) of the glandular cells was observed in the proliferative phase, but not in the secretory phase. Among several tumor suppressor gene products, only p27 was immunohistochemically observed in the secretory phase. (2) The expression of cyclins and cdks detected by immunoblotting in cultured endometrial glandular cells was reduced in progesterone treated cells. Conversely, the expression of p27 protein was increased in a dose dependent fashion in those cells treated with progesterone. (3) The expression of p27mRNA examined by Northern blotting analysis did not vary significantly between the proliferative and the secretory phases. (4) To evaluate the effect of progesterone on the proteolysis of p27 in cultured endometrial glands, amount of p27 protein treated with and without progcsterone was evaluated by immunoblotting in every 12 hours (up to 48 hours) after cycloheximide (a protein synthesis inhibitor) was induced. The result showed that the amount of p27 protein was more abundant in those cells treated with progesterone in every time course examined. (5) Forced expression of p27 protein by p27 expression plasmid in cultured endometrial glands induced increased expression of p27 and reduced expression of proliferating cell nuclear antigen (PCNA, an indicator of cell proliferation). In summary, the present study demonstrated that progesterone-induced reduced expression of cyclins/cdks, as well as elevated expression of p27 may be involved in the growth inhibition of endometrial glands.