The role of Hes genes in intestinal development, homeostasis and tumor formation.
Notch signaling regulates intestinal development, homeostasis and tumorigenesis, but its precise downstream mechanism remains largely unknown. Here we found that inactivation of the Notch effectors Hes1, Hes3 and Hes5, but not Hes1 alone, led to reduced cell proliferation, increased secretory cell formation and altered intestinal structures in adult mice. However, in Apc mutation-induced intestinal tumors, inactivation of Hes1 alone was sufficient for reducing tumor cell proliferation and inducing differentiation of tumor cells into all types of intestinal epithelial cells, but without affecting the homeostasis of normal crypts owing to genetic redundancy. These results indicated that Hes genes cooperatively regulate intestinal development and homeostasis and raised the possibility that Hes1 is a promising target to induce the differentiation of tumor cells.
Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Taro
T
Ueo
Itaru
I
Imayoshi
Taeko
T
Kobayashi
Toshiyuki
T
Ohtsuka
Hiroshi
H
Seno
Hiroshi
H
Nakase
Tsutomu
T
Chiba
Ryoichiro
R
Kageyama
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000378:metabolism; D017491:Genes, APC; D018398:Homeodomain Proteins / Q000235:genetics*; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D007420:Intestine, Large / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C411886:Hes3 protein, mouse; C489685:Hes5 protein, mouse