Notch-1 regulates pulmonary neuroendocrine cell differentiation in cell lines and in transgenic mice

被引:49
作者
Shan, Lin
Aster, Jon C.
Sklar, Jeffrey
Sunday, Mary E.
机构
[1] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA
[2] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA
[3] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Boston, MA 02115 USA
关键词
small cell lung carcinoma; tumor necrosis factor-alpha; antisense oligodeoxynucleotides; DOPA decarboxylase; neural cell adhesion molecule;
D O I
10.1152/ajplung.00052.2006
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
The notch gene family encodes transmembrane receptors that regulate cell differentiation by interacting with surface ligands on adjacent cells. Previously, we demonstrated that tumor necrosis factor-alpha (TNF) induces neuroendocrine (NE) cell differentiation in H82, but not H526, undifferentiated small cell lung carcinoma lines. We now test the hypothesis that TNF mediates NE cell differentiation in part by altering Notch gene expression. First, using RT-PCR, we determined that TNF treatment of H82, but not H526, transiently decreases notch-1 mRNA in parallel with induction of gene expression for the NE-specific marker DOPA decarboxylase (DDC). Second, we treated H82 and H526 with notch-1 antisense vs. sense oligodeoxynucleotides. Using quantitative RT-PCR and Western analyses we demonstrate that DDC mRNA and protein are increased in H82 by notch-1 antisense, whereas notch-1 mRNA and activated Notch-1 protein are decreased. mRNA for Hes1, a transcription factor downstream from activated Notch, is also decreased by Notch-1 antisense in H82 but not H526. After 7 days of Notch-1 antisense treatment, neural cell adhesion molecule (NCAM) immunoreactivity is induced in H82 but not H526. Third, we generated transgenic mice bearing notch-1 driven by the neural/NE-specific calcitonin promoter, which express activated Notch-1 in developing lung epithelium. Newborn NotchCal mouse lungs have high levels of hes1 mRNA, reflecting increased activated Notch, compared with wild-type. NotchCal lungs have decreased CGRP-positive NE cells, decreased protein gene product 9.5 (PGP9.5)-positive NE cells, and decreased gastrin-releasing peptide (GRP), CGRP, and DDC mRNA levels compared with normal littermates. Cumulatively, these observations provide further support for a role for Notch-1 signaling in regulating pulmonary NE cell differentiation.
引用
收藏
页码:L500 / L509
页数:10
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