Abstract
Notch3 is a transmembrane receptor and a member of the Notch signaling pathway essential for cellular differentiation in a variety of developing tissues in both invertebrates and vertebrates. Emerging data support the role of the Notch signaling pathway in tumorigenesis. We have previously demonstrated the expression of Notch3 in a subset of lung adenocarcinomas. To further elucidate the role of Notch3 in development of lung cancer, we established a transgenic mouse model in which the intracellular domain of Notch3 is expressed using the surfactant protein C promoter/enhancer. Constitutive expression of Notch3 in the peripheral epithelium in the developing lung resulted in altered lung morphology and delayed development, leading to perinatal lethality in these transgenic mice. Cell-specific markers and electron microscopy examination showed that the majority of the epithelial cells are undifferentiated, with some maturation of type II pneumocytes. No type I alveolar cells were evident. Metaplasia of undifferentiated cells in the terminal airways was also observed. Although the mice did not live long enough to assess tumor development, these findings demonstrate that ectopic expression of Notch3 in airway epithelium potentially contributes to the multistep evolution of lung cancer through the inhibition of terminal differentiation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Apelqvist A, Li H, Sommer L, Beatus P, Anderson DJ, Honjo T, Hrabe de Angelis M, Lendahl U and Edlund H . (1999). Nature, 400, 877–881.
Artavanis-Tsakonas S, Rand MD and Lake RJ . (1999). Science, 284, 770–776.
Beatus P, Lundkvist J, Oberg C and Lendahl U . (1999). Development, 126, 3925–3935.
Beckers J, Clark A, Wunsch K, Hrabe De Angelis M and Gossler A . (1999). Mech. Dev., 84, 165–168.
Bellavia D, Campese AF, Alesse E, Vacca A, Felli MP, Balestri A, Stoppacciaro A, Tiveron C, Tatangelo L, Giovarelli M, Gaetano C, Ruco L, Hoffman ES, Hayday AC, Lendahl U, Frati L, Gulino A and Screpanti I . (2000). EMBO J, 19, 3337–3348.
Capobianco AJ, Zagouras P, Blaumueller CM, Artavanis-Tsakonas S and Bishop JM . (1997). Mol. Cell Biol., 17, 6265–6273.
Dang TP, Gazdar AF, Virmani AK, Sepetavec T, Hande KR, Minna JD, Roberts JR and Carbone DP . (2000). J. Natl. Cancer Inst., 92, 1355–1357.
Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD and Sklar J . (1991). Cell, 66, 649–661.
Gallahan D and Callahan R . (1997). Oncogene, 14, 1883–1890.
Glasser SW, Korfhagen TR, Wert SE, Bruno MD, McWilliams KM, Vorbroker DK and Whitsett JA . (1991). Am. J. Physiol., 261, L349–L356.
Guan E, Wang J, Laborda J, Norcross M, Baeuerle PA and Hoffman T . (1996). J. Exp. Med., 183, 2025–2032.
Hogan BL . (1999). Cell, 96, 225–233.
Hogan BL and Yingling JM . (1998). Curr. Opin. Genet. Dev., 8, 481–486.
Ito T, Udaka N, Yazawa T, Okudela K, Hayashi H, Sudo T, Guillemot F, Kageyama R and Kitamura H . (2000). Development, 127, 3913–3921.
Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, Piga N, Chapon F, Godfrain C and Tournier-Lasserve E . (2000). J. Clin. Invest., 105, 597–605.
Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cecillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG and Tournier-Lasserve E . (1996). Nature, 383, 707–710.
Lardelli M, Williams R, Mitsiadis T and Lendahl U . (1996). Mech. Dev., 59, 177–190.
Linnoila RI, Zhao B, DeMayo JL, Nelkin BD, Baylin SB, DeMayo FJ and Ball DW . (2000). Cancer Res., 60, 4005–4009.
Llimargas M . (1999). Development, 126, 2355–2364.
Pear WS, Aster JC, Scott ML, Hasserjian RP, Soffer B, Sklar J and Baltimore D . (1996). J. Exp. Med., 183, 2283–2291.
Post LC, Ternet M and Hogan BL . (2000). Mech. Dev., 98, 95–98.
Rohn JL, Lauring AS, Linenberger ML and Overbaugh J . (1996). J. Virol., 70, 8071–8080.
Shelly LL, Fuchs C and Miele L . (1999). J. Cell Biochem., 73, 164–175.
Taichman DB, Loomes KM, Schachtner SK, Guttentag S, Vu C, Williams P, Oakey RJ and Baldwin HS . (2002). Dev. Dyn., 225, 166–175.
Ten Have-Opbroek AA . (1991). Exp. Lung Res., 17, 111–130.
Tournier-Lasserve E, Joutel A, Melki J, Weissenbach J, Lathrop GM, Chabriat H, Mas JL, Cabanis EA, Baudrimont M, Maciazek J and Bousser G . (1993). Nat. Genet., 3, 256–259.
Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML and Weinmaster G . (2001). Mech. Dev., 108, 161–164.
Warburton D, Schwarz M, Tefft D, Flores-Delgado G, Anderson KD and Cardoso WV . (2000). Mech. Dev., 92, 55–81.
Wert SE, Glasser SW, Korfhagen TR and Whitsett JA . (1993). Dev. Biol., 156, 426–443.
Zeng X, Gray M, Stahlman MT and Whitsett JA . (2001). Dev. Dyn., 221, 289–301.
Zhou L, Dey CR, Wert SE, Yan C, Costa RH and Whitsett JA . (1997). Dev. Dyn., 210, 305–314.
Acknowledgements
We thank Drs Joyce Johnson, Brigid Hogan, and Mildred Stahlman for their intellectual inputs. We especially thank Dr Jeff Whitsett not only for his construct, probe and antibodies, but also for his support and advice.
Author information
Authors and Affiliations
Corresponding author
Additional information
Grant Support: This study was supported by NIH SPORE for Lung Cancer 1 P50 CA090949. The EM CORE is supported by NIH grants CA68485 and DK20593.
Rights and permissions
About this article
Cite this article
Dang, T., Eichenberger, S., Gonzalez, A. et al. Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice. Oncogene 22, 1988–1997 (2003). https://doi.org/10.1038/sj.onc.1206230
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1206230
Keywords
This article is cited by
-
Multifaceted targeting strategies in cancer against the human notch 3 protein: a computational study
In Silico Pharmacology (2021)
-
Enhanced Notch3 signaling contributes to pulmonary emphysema in a Murine Model of Marfan syndrome
Scientific Reports (2020)
-
Local lung hypoxia determines epithelial fate decisions during alveolar regeneration
Nature Cell Biology (2017)
-
Lung Cancer Stem Cells and Implications for Future Therapeutics
Cell Biochemistry and Biophysics (2014)