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J. Biol. Chem., Vol. 275, Issue 27, 20700-20706, July 7, 2000
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From the Departments of Insulin-like growth factor-I (IGF-I)-mediated
signaling is thought to be involved in the regulation of multiple
cellular functions in different tumors including renal cell carcinoma
(RCC). Blocking IGF-I signaling by any of the several strategies
abolishes or delays the progression of a variety of tumors in animal
models. Herein, we demonstrate that in RCC cell lines, IGF-I-mediated signaling is found to be inhibited in the presence of wild type von
Hippel-Lindau (VHL) tumor suppresser gene. Moreover, molecular modeling
and biochemical approaches have revealed that
Inhibition of Insulin-like Growth Factor-I-mediated Cell
Signaling by the von Hippel-Lindau Gene Product in Renal Cancer*
,,
Pathology and
§ Molecular Computing Facility, Beth Israel Deaconess
Medical Center and Harvard Medical School, Boston, Massachusetts 02215 and ¶ Renal Section, Boston University Medical Center,
Boston, Massachusetts 02118
-domain of the VHL
gene product by interacting directly with protein kinase C
inhibits
its association with IGF-IR for downstream signaling. We also
demonstrated that RCC has IGF-I-mediated invasive activity where
protein kinase C is an important downstream molecule, and this
invasiveness can be blocked by wild type VHL. These experiments thus
elucidate a novel tumor suppresser function of VHL with its unique
kinase inhibitory domain.
*
This work was supported in part by National Institutes of
Health Grant CA78383 (to D. M.) and under terms of a contract from the National Foundation for Cancer Research.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Eugene P. Schonfeld Medical Research awardee from National
Kidney Cancer Association. To whom correspondence should be addressed: Dept. of Pathology, RN270H, Beth Israel Deaconess Medical Center and
Harvard Medical School, 99 Brookline Ave., Boston, MA 02215. Tel.:
617-667-7853; Fax: 617-667-3591; E-mail:
dmukhopa@caregroup.harvard.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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