NOTCH1 AND NOTCH2 INHIBIT MYELOID DIFFERENTIATION IN RESPONSE TO DIFFERENT CYTOKINES

We have compared the ability of two mammalian Notch homologs, mouse No tch1 and Notch2, to inhibit the granulocytic differentiation of 32D my eloid 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). Exp ression of the activated intracellular domain of Notch1 inhibits the d ifferentiation induced by G-CSF but not by GM-CSF; conversely, the cor responding 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 t his region, which we have termed the Notch cytokine response (NCR) reg ion. The NCR region is also associated with differences in posttransla tional modification and subcellular localization of the different Notc h molecules. These findings suggest that the multiple forms of Notch f ound in mammals have structural differences that allow their function to be modulated by Specific differentiation signals.