Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice.
The transcription factor achaete-scute homologue-1 (ASH1) is essential for neural differentiation during fetal development and is a cardinal feature of neuroendocrine (NE) tumors such as small cell lung cancer. To explore the potential of ASH1 to promote NE differentiation and tumorigenesis in the lung, we constitutively expressed the factor in nonendocrine airway epithelial cells using transgenic mice. Progressive airway hyperplasia and metaplasia developed beginning at 3 weeks of life. ASH1 potently enhanced the tumorigenic effect of SV40 large T antigen in airway epithelium. These doubly transgenic animals developed massive NE lung tumors, implying that ASH1 may cooperate with defects in p53, pRb, or related pathways in promoting NE lung carcinogenesis.
Linnoila
R I
RI
Cell and Cancer Biology Department, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Rockville, Maryland 20817, USA.
Zhao
B
B
DeMayo
J L
JL
Nelkin
B D
BD
Baylin
S B
SB
DeMayo
F J
FJ
Ball
D W
DW
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000633:toxicity; D051792:Basic Helix-Loop-Helix Proteins; D001980:Bronchi / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D003043:Cocarcinogenesis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000633:toxicity*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000235:genetics; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008679:Metaplasia / Q000209:etiology / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D018358:Neuroendocrine Tumors / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009490:Neurosecretory Systems / Q000166:cytology / Q000502:physiology; D011817:Rabbits; D016160:Retinoblastoma Protein / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D000952:Antigens, Polyomavirus Transforming; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse