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Modulation of the Binding of Progesterone Receptor to DNA by Polyamines¹

Division of Oncology, Department of Medicine, University of Minnesota Hospital and the Masonic Cancer Center, Minneapolis, Minnesota 55455

Putrescine, spermidine, and spermine are a group of small organic cations, collectively known as polyamines. They are present in all living cells, and their levels are generally increased in tumor cells. Progesterone receptor is a gene-regulatory protein that plays a major role in gestation and in hormonal responsiveness of breast cancer. We studied the effects of putrescine, spermidine, 2 lower homologues of spermidine, N¹- and N⁸-acetyl spermidines, spermine, and N¹-acetyl spermine on the sedimentation profile and DNA binding of progesterone receptor from rabbit uterus. Progesterone receptor, prepared in hypotonic buffer, sedimented at the 7S region of sucrose gradients. In the presence of 1 mM putrescine, a part of the receptor was converted to a 5S form. In the presence of 1 mM spermidine or 0.25 mM spermine, the receptor was completely transformed to the 5S form. The DNA binding of the 7S form of progesterone receptor was 7 ± 3%. After incubating this receptor with 1 mM putrescine, 1 mM spermidine, or 0.25 mM spermine, its DNA binding increased to 16 ± 4, 37 ± 3, and 44 ± 5%, respectively. The structural specificity of polyamines in facilitating the DNA binding of progesterone receptor was examined by using two spermidine homologues. The first homologue with one methylene group less than that of spermidine was as effective as spermidine in transforming progesterone receptor. Removal of two methylene groups, however, had a dramatic effect in reducing the efficacy of the resulting molecule to the level of putrescine. Taken together, our results show that natural polyamines are capable of modulating the binding of progesterone receptor to DNA. Since progesterone receptor is associated with the hormonal responsiveness of human breast cancer, polyamine levels in tumor cells might play an important role in the gene-regulatory function of progesterone receptor.

¹ This investigation was supported in part by a New Investigator Research Award from the NIH (CA-42439-02 to T. T.) and by the Minnesota Medical Foundation (D. T. K.).

² To whom requests for reprints should be addressed, at the University of Minnesota, Division of Medical Oncology, Box 168, UMHC, 420 Delaware Street, S.E., Minneapolis, MN 55455.

Received 10/19/87. Accepted 11/30/87.