Compound disruption of smad2 accelerates malignant progression of intestinal tumors in apc knockout mice.
Smad2 is a receptor-regulated Smad that is activated specifically by transforming growth factor beta and activin signaling. We disrupted the mouse Smad2 gene by gene targeting. Homozygous Smad2 mutant mice died around E8.5 with impaired visceral endoderm function and deficiency of mesoderm formation. Heterozygotes were fertile and had no apparent abnormality up to at least 1 1/2 year of age. To examine the role of Smad2 inactivation in the process of carcinogenesis, we prepared compound heterozygous mice, which carry both Apc and Smad2 mutations on the same chromosome in the cis-configuration. Compound inactivation of Smad2 in heterozygous Apc mutant mice did not change the total number of intestinal tumors but increased sudden death from intestinal obstruction caused by extremely large tumors. Furthermore, histological examination revealed that Apc/Smad2 cis-compound heterozygotes developed multiple invasive cancers that had never been observed in Apc single heterozygotes. These results indicate that loss of Smad2 does not initiate tumorigenesis by itself but accelerates malignant progression of tumors to invasive cancer in the late stages of carcinogenesis.
Hamamoto
Toshiaki
T
Departments of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan.
Beppu
Hideyuki
H
Okada
Hitoshi
H
Kawabata
Masahiro
M
Kitamura
Tadaichi
T
Miyazono
Kohei
K
Kato
Mitsuyasu
M
D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D051899:Smad2 Protein; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics*
D004268:DNA-Binding Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators