B-1 cells (formerly Ly-1+ or CD5+ B-cells) are distinguished from conventional B (B-2) cells by numerous phenotypic functional, and growth-related characteristics. B-1 cells are strongly associated with malignant transformation and autoimmune diseases. Despite much descriptive information about this lineage, the molecular basis for B-1 cell features has not been clarified. The recent discovery in Dr. Rothstein's laboratory that B-1 cells constitutively express an activated STAT (Ptyr705STAT3) transcription factor (whereas B-2 cells do not) provides a new tool for understanding the development and behavior of the B-1 lineage. The long-term objective of this work is to elucidate the underlying mechanism responsible for B-1 cell features. The goals of the present application are to evaluate activated STAT3 as a sign of, and as a determinant of, B-1 development and function, and to test the hypothesis that activated STAT3 expression is responsible, at least in part, for the nature of B-1 cells. This will be accomplished through four specific aims. 1. Determine whether the lineage-specific difference in Ptyr705STAT3 expression characterizes all stages of B-1 cell development, and whether Ptyr705STAT3 is found in B-1-related populations; 2. Assess the extent to which STAT3 directs B-1 cell development by analyzing transgenic mice that overexpress activated STAT3, activated STAT3f, and dominant negative STAT3; 3. Clone the murine cyclin D2 promoter that responds to PMA alone in B-1 cells and determine the role of constitutive Ptyr705STAT3 expression in promoting cyclin D2 transcription; and 4. Identify the kinase responsible for phosphorylating STAT3 inducibly in B-2 cells and constitutively in B-1 cells.
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