An achaete-scute homologue essential for neuroendocrine differentiation in the lung.
In Drosophila and in vertebrates, the achaete-scute family of basic helix-loop-helix transcription factors plays a critical developmental role in neuronal commitment and differentiation. Relatively little is known, however, about the transcriptional control of neural features in cells outside a neuronal context. A minority of normal bronchial epithelial cells and many lung cancers, especially small-cell lung cancer, exhibit a neuroendocrine phenotype that may reflect a common precursor cell population. We show here that human achaete-scute homologue-1 (hASH1) is selectively expressed in normal fetal pulmonary neuroendocrine cells, as well as in the diverse range of lung cancers with neuroendocrine features. Strikingly, newborn mice bearing a disruption of the ASH1 gene have no detectable pulmonary neuroendocrine cells. Depletion of this transcription factor from lung cancer cells by antisense oligonucleotides results in a significant decrease in the expression of neuroendrocrine markers. Thus, a homologue of Drosophila neural fate determination genes seems to be necessary for progression of lung epithelial cells through a neuroendocrine differentiation pathway that is a feature of small-cell lung cancer, the most lethal form of human lung cancer.
Borges
M
M
The Oncology Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Linnoila
R I
RI
van de Velde
H J
HJ
Chen
H
H
Nelkin
B D
BD
Mabry
M
M
Baylin
S B
SB
Ball
D W
DW
D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000196:embryology / Q000294:innervation; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009490:Neurosecretory Systems / Q000166:cytology; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse