Intestinal overexpression of ZNF148 suppresses ApcMin/+ neoplasia.
ZNF148 (ZBP-89, Zfp148) is a multifunctional transcription factor expressed at low levels in most tissues. When overexpressed in gastrointestinal cancer cell lines, ZNF148 inhibits cellular proliferation and induces apoptosis. We sought to determine whether intestinal ZNF148 overexpression would abrogate adenoma development in the ApcMin/+ mouse, i.e., whether ZNF148 is a tumor suppressor. The 13-kb villin promoter was spliced upstream of the ZNF148 cDNA to generate transgenic villin-ZNF148 (ZNF148TgVZ) mice. Intestinal mucosal ZNF148 expression was elevated in four of five ZNF148(TgVZ) lineages and correlated with increased caspase-3 expression and activation. In addition, DNA fragmentation was increased in ZNF148TgVZ mice relative to wild-type littermates. These results suggested that increased intestinal ZNF148 expression induces apoptosis. ZNF148TgVZ mice were crossed with ApcMin/+ mice to assess the biological significance of intestinal ZNF148 overexpression. The presence of the ZNF148TgVZ allele in ApcMin/+ mice correlated with reduced gastrointestinal bleeding at 5 weeks, a 50% reduction in adenoma burden at 20-22 weeks, and prolonged survival (median survival of 33.5 days vs. 21.5 days), relative to nontransgenic littermates. These data suggest that enhanced ZNF148 expression activates intestinal apoptosis and thereby mitigates disease burden in ApcMin/+ mice. They also suggest that ZNF148 is a therapeutic target to inhibit colon cancer development.
Law
David J
DJ
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, 48109-2200, USA.
Labut
Edwin M
EM
Merchant
Juanita L
JL
D000236:Adenoma / Q000378:metabolism / Q000401:mortality; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology*; D005767:Gastrointestinal Diseases / Q000235:genetics / Q000401:mortality / Q000517:prevention & control; D006470:Hemorrhage / Q000235:genetics / Q000401:mortality / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000378:metabolism / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010375:Pedigree; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D047368:Tumor Burden / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000378:metabolism / Q000502:physiology
D025601:Adenomatous Polyposis Coli Protein; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C110951:ZNF148 protein, human