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Identification of the coding sequences responsible for Tsc2-mediated tumor suppression using a transgenic rat system

Shuji Momose1, Toshiyuki Kobayashi, Hiroaki Mitani

  • 1Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo, Japan.

Human Molecular Genetics
|November 6, 2002
PubMed

Insights

Researchers identified key regions of the tuberous sclerosis-2 (Tsc2) gene product, tuberin, essential for preventing kidney cancer and embryonic lethality in Eker rats. Tuberin can suppress tumors independently of binding to hamartin.

Area of Science:

  • Genetics and Molecular Biology
  • Oncology
  • Developmental Biology

Background:

  • Hereditary renal carcinomas in Eker rats stem from retrotransposon insertion in the tuberous sclerosis-2 (Tsc2) gene.
  • Previous studies established a transgenic Eker rat model that suppressed tumor development and embryonic lethality by introducing a wild-type Tsc2 gene.
  • The precise in vivo functions of the Tsc2 protein, tuberin, remain incompletely understood.

Purpose of the Study:

  • To elucidate the functional domains of Tsc2 in vivo using a transgenic Eker rat model.
  • To identify the minimal region of tuberin required for tumor suppression and rescue from embryonic lethality.

Main Methods:

  • Generation of transgenic Eker rats carrying deletion mutants of the Tsc2 gene.
  • Analysis of renal carcinogenesis suppression and embryonic lethality rescue in these mutant rats.
  • Assessment of Tsc2 deletion mutant protein expression levels and Tsc1 (hamartin) binding capability.

Main Results:

  • A transgene encoding the C-terminal region (amino acids 1425-1755) of tuberin suppressed renal carcinogenesis, with suppression level correlating to expression.
  • This C-terminal Tsc2 transgene product did not bind to Tsc1 (hamartin).
  • A transgene lacking the C-terminus (amino acids 1-1755) completely suppressed renal carcinogenesis and partially rescued homozygous mutants from embryonic lethality.

Conclusions:

  • The minimal region of tuberin necessary for tumor suppression has been determined, demonstrating a quantitative suppressive effect.
  • Tuberin can function as a tumor suppressor even without binding to hamartin.
  • The functional domains of tuberin required for preventing embryonic lethality may differ from those for suppressing renal carcinogenesis.

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