THE CONTRIBUTION OF SMC TO THE PATHOLOGY OF GASTROINTESTINAL STROMAL TUMORS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project is based on the observations that Notch signaling is an important regulator of smooth muscle cell (SMC) differentiation and cell cycle progression, and that gastrointestinal stromal tumors (GIST) share molecular markers with SMC. Human GIST cells express Notch receptors, and their growth is inhibited by gamma secretase inhibitors that block endogenous Notch signaling. Challenges associated with the GIST focus are: limited viral transduction efficiency for signaling studies, and until recently, the availability of only one isolate of GIST cells. Therefore, in the last funding period we focused mainly on human primary SMC to address basic molecular mechanisms by which Notch signaling regulates SMC differentiation phenotypes. Our findings in normal cells will be applied to the idea that cell differentiation therapies related to GIST may be one mechanism to stop abnormal growth and progression of GIST pathologies. Activation of Notch signaling in human SMC was accomplished with adenoviral transduction of constitutively active intracellular domain forms of the Notch receptors. Secondly, expression of the Notch target genes, HRT1 and HRT2, was used to understand the functions of these bHLH factors in Notch-mediated SMC regulation. Analysis of SMC differentiation marker expression, transcription, turnover, and stability determined that Notch provides a strong signal for the SMC differentiated phenotype. Surprisingly, however, HRT activity antagonizes Notch signaling, and suppresses the SMC differentiated phenotype. These findings provide the framework for a novel Notch negative feedback mechanism that may serve to regulate the balance between the mature phenotype and the transitional phenotype necessary for vascular remodeling.