N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo

Biochem Biophys Res Commun. 2007 May 11;356(3):693-8. doi: 10.1016/j.bbrc.2007.03.036. Epub 2007 Mar 13.

Abstract

The Eker rat is an animal model of renal carcinogenesis and carries a transposon insertion in the Tsc2 (tuberous sclerosis-2) gene. We previously generated transgenic Eker rats and identified coding sequences in the Tsc2 gene that are responsible for suppression of renal carcinogenesis in Eker rats. Tsc2-RGH, a transgene that expresses the carboxy terminal region (amino acids 1425-1755) of the Tsc2 product (tuberin), partially suppressed renal carcinogenesis. However, Tsc2-DRG, which expresses a mutant tuberin lacking the carboxy-terminal region (Delta aa 1425-1755), did not suppress renal carcinogenesis. Here, we found that introduction of both Tsc2-RGH and Tsc2-DRG in Eker rats completely suppressed renal carcinogenesis and rescued homozygous (Tsc2(Ek/Ek)) mutants from embryonic lethality in a complementary manner. Co-introduction of Tsc2-RGH and Tsc2-DRG, but not introduction of either alone, efficiently suppressed phosphorylation of p70 S6K. Thus, the functional domains of N-terminal hamartin binding and C-terminal tumor suppression in tuberin can separate in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Ethylnitrosourea
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTPase-Activating Proteins / metabolism*
  • Kidney / embryology
  • Kidney Neoplasms / chemically induced
  • Kidney Neoplasms / genetics
  • Protein Structure, Tertiary
  • Rats
  • Signal Transduction / physiology
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / chemistry*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • GTPase-Activating Proteins
  • Tsc2 protein, rat
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Extracellular Signal-Regulated MAP Kinases
  • Ethylnitrosourea