Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / toxicity
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Basic Helix-Loop-Helix Transcription Factors
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Bronchi / pathology
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Carcinoma, Non-Small-Cell Lung / etiology*
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Differentiation / physiology
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Cell Division / physiology
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Cocarcinogenesis
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / toxicity*
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Epithelial Cells / pathology
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Female
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Humans
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Hyperplasia / etiology
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Hyperplasia / genetics
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Lung / pathology
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Lung Neoplasms / etiology*
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology
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Metaplasia / etiology
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Metaplasia / genetics
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Mice
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Mice, Inbred ICR
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Mice, Transgenic
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Neuroendocrine Tumors / etiology*
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Neuroendocrine Tumors / genetics
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Neuroendocrine Tumors / pathology
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Neurosecretory Systems / cytology
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Neurosecretory Systems / physiology
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Rabbits
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Retinoblastoma Protein / physiology
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Transcription Factors / genetics*
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Transcription Factors / toxicity*
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Tumor Suppressor Protein p53 / physiology
Substances
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ASCL1 protein, human
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Antigens, Polyomavirus Transforming
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Ascl1 protein, mouse
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Retinoblastoma Protein
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Transcription Factors
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Tumor Suppressor Protein p53