Research
Signal Transduction of Cytokine Growth Factors and Target Gene Activation and Functions
IL-3 and GM-CSF are required for the proliferation, differentiation, survival and functions of some hematopoietic cells. We have been interested in studying mechanisms responsible for the survival functions of IL-3/GMCSF by looking for survival genes that are activated by these two cytokines. Two genes (mcl-1 and osteopontin) have been identified and their roles in cytokine survival effects have been extensively studied. By promoter analysis, we have further delineated the signaling pathways from receptor activation to mcl-1 gene transcription. To further delineate the signaling and regulation of mcl-1 gene in vivo, a few promoter mutant knockin mice have been generated and they are currently under characterization.
To further delineate Mcl-1's biological function(s), the yeast two-hybrid approach has been employed to identify Mcl-1-interacting protein(s). Two proteins (TCTP and Tom70) have thus been characterized. While TCTP enhances Mcl-1's stability, Tom70 facilitates Mcl-1 targeting to mitochondria. Our current direction for this part is to characterize the physiological significance of these protein-protein interactions by biochemical analyses as well as by generation of a few mutant mouse models.
Other than presence in the hematopoietic cell systems, many cytokine growth factors are expressed in the uterus during pregnancy where they regulate embryo implantation and survival through an unknown mechanism. To identify additional cytokines that may be involved in this process, a subtraction cloning approach using the SAGE method has been employed. A few candidate genes from this screen are currently under characterization.
