Certain phorbol esters, polar solvents and retinoids have been identified as in vitro and in vivo inducers of human myeloid leukemia cell differentiation. However, the mechanisms by which these diverse classes of agents induce differentiation remain unclear. Our previous studies focused on transcriptional activation of the c-jun and EGR-1 early response genes. The available evidence supports the involvement of these genes in induction of the differentiated myeloid phenotype. Moreover, identification of the cis-acting elements responsible for activation of c-jun and EGR-1 provided the basis for demonstrating involvement of a Raf-1/MAP kinase/pp90rsk signaling cascade. Other studies supported by this grant have provided evidence that differentiation of myeloid leukemia cells is associated with induction of apoptosis. The proposed work will extend the recent finding that differentiation of myeloid leukemia cells includes induction of the stress activated protein (SAP, JNK) kinase. Our hypothesis is that activation of the SAP kinase pathway may contribute to the """"""""switch"""""""" that directs a cell to differentiate rather than proliferate. The finding that the nuclear c-Abl protein tyrosine kinase, which acts upstream to SAP kinase, is activated by differentiating agents has provided the basis for studying involvement of a c-Abl- greater SAP kinase cascade. The formation of a nuclear complex involving c-Abl, a Src-like kinase and a protein tyrosine phosphatase will be studied as a mechanism for regulating the differentiation program. The recent findings that SAP kinase contributes to induction of apoptosis provides further support for the involvement of this pathway in a process of terminal differentiation. These issues will be addressed in the proposed work.
The Specific Aims are: 1) To define the signaling mechanisms responsible for induction of SAP kinase activity in myeloid leukemia cell differentiation; 2) To study the functional significance of a novel nuclear signaling cascade in differentiation of myeloid leukemia cells; 3) To study the functional involvement of Src-like protein tyrosine kinases in induction of leukemic cell differentiation; 4) To define the signaling events responsible for apoptosis associated with terminal differentiation of myeloid leukemia cells.
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