N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo.
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.
Momose
Shuji
S
Department of Pathology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda-tsujimichi, Kawagoe, Saitama 350-8550, Japan.
Kobayashi
Toshiyuki
T
Tada
Norihiro
N
Itoyama
Shinji
S
Hino
Okio
O
D000818:Animals; D030801:Animals, Genetically Modified; D005038:Ethylnitrosourea; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D007668:Kidney / Q000196:embryology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*
D020690:GTPase-Activating Proteins; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D005038:Ethylnitrosourea