Significance of proneural basic helix-loop-helix transcription factors in neuroendocrine differentiation of fetal lung epithelial cells and lung carcinoma cells T. Ito1, N. Udaka1, M. Ikeda1, T. Yazawa1, R. Kageyama2 and H. Kitamura1 1Department of Pathology, Yokohama City University School of Medicine, and 2Virus Research Institute, Kyoto University, Kyoto, Japan Offprint requests to: Dr. Takaaki Ito, Department of Pathology, Yokohama City University School of Medicine, 3-9 Fuku-Ura, Kanazawa-ku, Yokohama 236-0004, Japan. Fax: +81-45-789-0588. e-mail: takaito@med.yokohama-cu.ac.jp
Summary. In this
brief review article, we describe how cell fate determination
by which the airway epithelial cells become neuroendocrine or
non-neuroendocrine is regulated by a network of basic helix-loop-helix
transcription (bHLH) factors in a similar manner to neuronal differentiation,
and how this system could work to determine cell differentiation
of human lung carcinomas. Immunohistochemical studies reveal that
mammalina achaete-scute complex homologue (Mash)1 is expressed
in pulmonary neuroendocrine cells (PNEC), while hairy and Enhancer
of split (Hes)1 is expressed in pulmonary non-neuroendocrine cells
(non-PNEC). Studies using gene-deficient mice for the bHLH factors
revealed that in Mash1 homozygous null mice no PNEC are detected,
while PNEC increase markedly in Hes1 homozygous null mice. These
observations suggest that Mash1 is an essential positive factor
for neuroendocrine differentiation of lung epithelium, and that
Hes1 is one of the repressive factors for neuroendocrine differentiation.
Moreover, immunohistochemical studies revealed that Notch receptors
are detected in non-PNEC, and thus the Notch signalling pathway
could play a role in the determination of airway epithelial cell
differentiation. Key words: Cell
differentiation, Basic helix-loop-helix, Mash1, Hes1, Small cell
carcinoma |