No effects of Smad2 (madh2) null mutation on malignant progression of intestinal polyps in Apc(delta716) knockout mice.
The loss of heterozygosity (LOH) in human chromosome 18q21 is found at high frequencies in advanced pancreatic and colorectal cancers. Several candidate tumor suppressor genes, such as SMAD2, SMAD4, and DCC, are located in this region. The homologues of these genes in the mouse are also clustered on chromosome 18. Mutations in the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis, and we earlier constructed a mouse model for familial adenomatous polyposis, Apc(delta716). Although human APC is located on chromosome 5q, mouse Apc is on chromosome 18, 30 cM proximal to the Dcc-Smad4-Smad2 locus. Taking advantage of this fact, we constructed previously a cis-compound Apc(delta716) Smad4 mutant, the intestinal polyps of which progress to very invasive adenocarcinomas. To determine whether Smad2 mutations play similar roles in malignant progression, here we constructed compound mutant mice carrying Apc and Smad2 knockouts in the cis configuration. In contrast to the cis-compound Apc(delta716) Smad4 heterozygotes, the polyps in the cis-compound Apc(delta716) Smad2 heterozygotes showed no difference in the number, size, or histopathology from the polyps in the simple Apc(delta716) heterozygotes. These results suggest that, on human chromosome 18q21, the SMAD4 LOH plays a more significant role, and SMAD2 LOH is insufficient to cause malignant progression of colonic polyps.
Takaku
Kazuaki
K
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Wrana
Jeffrey L
JL
Robertson
Elizabeth J
EJ
Taketo
Makoto M
MM
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D017491:Genes, APC; D006579:Heterozygote; D007417:Intestinal Polyps / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics*
D004268:DNA-Binding Proteins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators