The stress kinase mitogen-activated protein kinase kinase (MKK)7 is a negative regulator of antigen receptor and growth factor receptor-induced proliferation in hematopoietic cells

The dual specificity kinases mitogen-activated protein kinase (MAPK) kinase (MKK)7 and MKK4 are the only molecules known to directly activate the stre ss kinases stress-activated protein kinases (SAPKs)/c-jun N-terminal kinase s (JNKs) in response to environmental or mitogenic stimuli. To examine the physiological role of MKK7 in hematopoietic cells, we used a gene targeting strategy to mutate MKK7 in murine T and B cells and non-lymphoid mast cell s. Loss of MKK7 in thymocytes and mature B cells results in hyperproliferat ion in response to growth factor and antigen receptor stimulation and incre ased thymic cellularity. Mutation of MKK7 in mast cells resulted in hyperpr oliferation in response to the cytokines interleukin (IL)-3 and stem cell f actor (SCF). SAPK/JNK activation was completely abolished in the absence of MKK7, even though expression of MKK4 was strongly upregulated in mkk7(-/-) mast cell lines, and phosphorylation of MKK4 occurred normally in response to multiple stress stimuli. Loss of MKK7 did not affect activation of extr acellular sign al-regulated kinase (ERK)1/2 or p38 MAPK. mkk7(-/-) mast cel ls display reduced expression of junB and the cell cycle inhibitor p16INK4a and upregulation of cyclinD1. Reexpression of p16INK4a in mkk7(-/-) mast c ells abrogates the hyperproliferative response. Apoptotic responses to a va riety of stimuli were not affected. Thus, MKK7 is an essential and specific regulator of stress-induced SAPK/JNK activation in mast cells and MKK7 neg atively regulates growth factor and antigen receptor-driven proliferation i n hematopoietic cells. These results indicate that the MKK7-regulated stres s signaling pathway can function as negative regulator of cell growth in mu ltiple hematopoietic lineages.