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Mol Cell Biol, April 1998, p. 2324-2333, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Notch1 and Notch2 Inhibit Myeloid Differentiation in Response to Different Cytokines

Anna Bigas,1,dagger David I. K. Martin,1,2 and Laurie A. Milner1,2,*

The Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024,1 and Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 981952

Received 21 July 1997/Returned for modification 8 September 1997/Accepted 14 January 1998

We have compared the ability of two mammalian Notch homologs, mouse Notch1 and Notch2, to inhibit the granulocytic differentiation of 32D myeloid progenitor cells. 32D cells undergo granulocytic differentiation when stimulated with either granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Expression of the activated intracellular domain of Notch1 inhibits the differentiation induced by G-CSF but not by GM-CSF; conversely, the corresponding domain of Notch2 inhibits differentiation in response to GM-CSF but not to G-CSF. The region immediately C-terminal to the cdc10 domain of Notch confers cytokine specificity on the cdc10 domain. The cytokine response patterns of Notch1 and Notch2 are transferred with this region, which we have termed the Notch cytokine response (NCR) region. The NCR region is also associated with differences in posttranslational modification and subcellular localization of the different Notch molecules. These findings suggest that the multiple forms of Notch found in mammals have structural differences that allow their function to be modulated by specific differentiation signals.

* Corresponding author. Mailing address: The Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., MS C3-168, P.O. Box 19024, Seattle, WA 98109-1024. Phone: (206) 667-4104. Fax: (206) 667-6524. E-mail: lmilner{at}fred.fhcrc.org.

dagger Present address: Institut de Recerca Oncologica, Hospital Duran y Reynals, Barcelona, Spain.




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