EMAP II Regulation of Pulmonary Cell Proliferation

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DESCRIPTION (provided by applicant): Endothelial-Monocyte Activating Polypeptide (EMAP) II is a unique, leaderless, single chain polypeptide protein first identified from murine fibrosarcoma. In its precursor form, it is 34-kDa molecule and is processed by unknown mechanisms to a mature 21-kDa form. Mature EMAP II (mEMAP II) is an extracellular molecule that is known to activate endothelial cells, neutrophils and mononuclear phagocytes and appears to be a proinflammatory mediator with the capacity to prime tumor vasculature for a locally destructive process or be anti-angiogenic in its own capacity. We recently demonstrated that mEMAP II is a director of neovascularization in the developing lung as its expression is inversely correlated to periods of vascularization and introduction of recombinant mEMAP II in a murine allograft model of lung development profoundly disrupts alveolar-capillary growth. In contrast to extracellular mEMAP II, considerably less is known regarding the function of the intracellular proform (pEMAP II). Our preliminary data suggest that pEMAP II must have an important intracellular function prior to its secretion because: 1) its levels are tightly regulated in relationship to the cell cycle, 2) it undergoes nucleocytoplasmic partitioning, and 3) it is post-translationally modified. Accordingly, specific alms of this proposal are: 1) To determine the role of intracellular pEMAP II's subcompartmentalization and post-translational modification within the cell cycle; 2) To determine the mechanism that affects intracellular processing of pEMAP II; 3) To determine the mechanism by which EMAP II is secreted; and 4) To identify the extracellular determinants of the pEMAP II / mEMAP II balance in regulating lung growth. Thus, identifying factors that govern the intracellular processing of pEMAP II and ultimately affect its secretion are critical determinants of the biological role of EMAP II and will provide insight into the determinants by which a balance of pEMAP II / mEMAP II can affect lung development.