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Inhibition of DNA Synthesis in rat hepatocytes by Platelet-derived Type ß Transforming Growth Factor¹

Departments of Medical Oncology and Experimental Therapeutics [B. I. C.] and Cytogenetics and Cytology [I. H.], City of Hope National Medical Center, Duarte, California 91010, and Departments of Cell Biology, Mayo Clinc/Foundation [E. L. B., H. L. M.], Rochester, Minnesota 55901

Platelet-derived type ß transforming growth factor (TGFß) is a potent inhibitor of DNA synthesis in primary monolayer cultures of adult rat hepatocytes. TGFß induced a 50% inhibition of epidermal growth factor (EGF)-mediated DNA synthesis at approximately 5 x 10¹² M. This inhibition did not appear to be due to a delay in the peak of DNA synthesis or a toxic action, nor could it be overcome by increasing concentrations of the mitogens EGF, insulin, or glucagon. Inhibition was observed either when TGFß and EGF were continuously present together in the culture medium or when TGFß was added to the hepatocyte cultures after removal of the EGF stimulant. This observation together with a lack of an inhibitory effect of TGFß on the binding of ¹²⁵I-labeled EGF to hepatocytes in culture, suggests that the inhibitory action of TGFß was not caused by a direct competition with EGF at the cell surface. TGFß could not inhibit DNA synthesis once it had begun; however, the inhibitory action of TGFß could be partially overcome by increasing amounts of conditioned medium produced by normal hepatocytes. Specific saturable receptors for TGFß were found on the normal rat hepatocytes, but specific binding could not be detected on hepatocytes from regenerating liver. TGFß is thus a potent inhibitor of EGF-induced DNA synthesis in adult rat hepatocytes. Its significance for growth control in vivo has yet to be assessed.

¹ Support for this work was provided in part by USPHS Grants CA-433572 and CA 27217 from the National Cancer Institute.

² To whom requests for reprints should be addressed, at Department of Medical Oncology, City of Hope Medical Center, 1500 E. Duarte Road, Duarte, CA 91010.

Received 10/15/85. Revised 2/ 6/86. Accepted 2/ 7/86.

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