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Insulin-like Growth Factor 1 Receptors Are Increased in Estrogen-induced Kidney Tumors¹

Sealy Center for Molecular Science, University of Texas Medical Branch, Galveston, Texas 77550 [S. N.]; and Department of Environmental Health Sciences, University of Alabama, Birmingham, Alabama 35294 [D. R.]

We have previously demonstrated that membrane receptor protein tyrosine kinase(s) activities are higher in estrogen-induced kidney tumors in comparison with such activities in the normal kidney. In the present work we have investigated the growth factor binding sites in estrogen-induced kidney tumor and in normal kidney membranes in an attempt to understand the mechanism of activation of membrane protein tyrosine kinase(s) and their possible relationship to the induction of estrogen-induced tumors. The characteristics of the normal hamster kidney membrane insulin-like growth factor 1 (IGF-1) receptor are similar to those reported for kidney and extrarenal tissues of other rodents. The binding of ¹²⁵I-IGF-1 to the normal kidney or tumor membranes was saturable and dependent on time, protein, pH, and temperature. The binding of ¹²⁵I-IGF-1 to the tumor membranes was significantly higher when compared to the binding activity of the membranes obtained from age-matched normal kidney. The Scatchard analysis of the binding data of both tumor and normal kidney revealed a single class binding site for IGF-1 with K_d of 1.7 and 1.8 nM and maximum binding capacities of 4150 and 2050 fmol/mg protein, respectively. Therefore, the difference observed in ¹²⁵I-IGF-1 binding between tumor and normal kidney membranes was due to an increase in the number of IGF-1 binding sites with no change in the affinity of receptors for IGF-1. An enhanced level of IGF-1 receptors in tumor membranes also was visualized by autoradiography following affinity labeling of membrane proteins subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Under reducing conditions of electrophoresis, two molecular bands of M_r 240,000 and M_r 130,000 were evident. The M_r 130,000 band represents the subunit of IGF-1 receptors, and the M_r 240,000 band may represent the aggregates of the receptor subunits which were not reduced completely. IGF-1 stimulated normal kidney or tumor membrane protein tyrosine kinase(s) (wheat germ lectin agarose-purified membrane proteins) in a dose-dependent fashion. Therefore, the alteration of IGF-1 binding activity of the tumor membrane receptors and stimulation of IGF-1-mediated membrane protein tyrosine kinase activity in tumor tissues suggest that events coupled to this membrane receptor may play a role in estrogen stimulation of renal carcinoma.

¹ This research was supported by a grant from the NIH (CA52584).

² To whom all requests for reprints should be addressed, at Department of Environmental Health Sciences, University of Alabama, 720 S. 20th St., Birmingham, AL 35294-0008.

Received 12/ 4/92. Accepted 3/12/93.

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