We have discovered a new family of nucleoproteins termed LEKs. These proteins are very large (350 kD) and have a conserved array of protein domains that include 11 leucine zippers, a spectrin repeat, an atypical Rb-binding domain, a myc-type HLH-binding domain and a nuclear localization signal (NLS). Published data confirms the functional complexity of this family. Expression patterns of various LEK proteins are dynamic and variant with reference to cell type and subcellular localization during mitosis. Importantly, any disruption of LEK protein function tested thus far disrupts cell division and/or differentiation. In addition, LEK proteins appear to play critical roles in heart development. One family member, LEK1, present in mice and the subject of this application, is ubiquitously expressed in dividing embryonic cells during their differentiation. LEK1 is down regulated during embryogenesis and is not expressed in cells of the adult. LEK1 function is dependent on proteolytic cleavage to produce cyto-LEK that is retained in the cytoplasm of cells and nuc-LEK that is translocated to the nucleus. Our previous and new data show that disruption of LEK1 function slows or halts cell cycle progression, including that of cardiac myocytes and the nuc-LEK interacts with Rb members, known regulators of cell division and differentiation. In addition, we show that nuc-LEK can transactivate muscle- and cardiac-specific gene expression. This leads to the hypothesis that LEK1 plays a critical role(s) in regulation of cell division and differentiation during embryogenesis and especially in heart development. The goal of this proposal is to determine the function of LEK1 and nuc-LEK in heart development. Data from the proposed studies will help determine the role of this novel regulator of cardiac myocyte development.
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