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Transforming Growth Factor ß₁ Induction Is Associated with Transforming Growth Factors ß₂ and ß₃ Down-Modulation in 12-O-Tetradecanoylphorbol-13-acetate-induced Skin Hyperplasia¹

Department of Pathology, Yale Medical School, New Haven, Connecticut 06510 [J. S. E., F. D., C. M., G. P. D.], and Laboratory of Chemoprevention, National Cancer Institute, Bethesda, Maryland 20892 [K. C. F.]

Acute treatment of mouse skin with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) induces marked epidermal hyperplasia, which is well evident by 24 h and maximal by 48–72 h. These effects are associated with the early induction of transforming growth factor (TGF) ß₁ expression in the epidermis. We show here that, in contrast to TGF-ß₁, TGF-ß₂, and TGF-ß₃, skin expression is significantly down-modulated in response to TPA. TGF-ß₃ RNA levels decreased by 6 h of treatment but returned to normal or even higher levels at later times. The TGF-ß₃ protein could be detected immunohistochemically in both dermis and epidermis in control skins and at early times of TPA treatment. However, at later times, TGF-ß₃ was found only in dermal cells and not in the epidermis. TGF-ß₂ RNA expression was found to be significantly down-modulated by 24 h of TPA treatment and remained low even at later times. Thus, differential control of the 3 TGF-ß isoforms appears to be a likely determinant of normal skin homeostasis and could be at least partially responsible for TPA-induced skin hyperplasia.

¹ This work was supported by NIH Grants AR 39190 and CA 16038.

² Present address: Cutaneous Biology Research Center, Dermatology Department, Harvard Medical School, Massachusetts General Hospital East, Charlestown, MA 02129.

³ To whom requests for reprints should be addressed.

Received 3/15/93. Accepted 9/15/93.

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