Transcriptional Regulation of Notch/MAML Signaling in Development and Cancers
Our broad research interests are to understand the molecular events responsible for stem cell maintenance, cell fate determination and oncogenic transformation. We are particularly interested in a specific signal transduction pathway mediated by the Notch receptors, the Notch signaling pathway. Notch signaling is one of a few highly conserved cell-fate determination pathways that are essential for the development of almost all tissues. Interestingly, this pathway also has emerging roles in regulating self-renewal of normal and cancer stem cells. Abnormalities in the components of this pathway are associated with a number of developmental disorders and cancer.
We previously have identified a novel family of three transcriptional co-activators, the mastermind-like genes (MAML) and showed that they are essential for mediating Notch effects via co-activation of transcription (Nat. Genet. 2000; Mol. Cell Biol. 2002; Gene 2004). When activated by ligand binding, the Notch receptor is cleaved and the intracellular domain of Notch receptor (ICN) translocates to the nucleus. ICN then interacts with the transcription factor CSL and recruits the MAML co-activator proteins, regulating the transcription of specific target genes (Nat. Genet. 2000; Mol. Cell Biol. 2002; Gene 2004). Our studies also have implicated MAML family members in tumorigenesis. For example, MAML proteins are binding partners for the human papilloma virus (HPV) E6 oncoproteins, which are widely implicated in cervical cancer transformation. Additionally, one MAML family member, the MAML2 gene, mutates as a result of a recurring chromosomal translocation found in a subset of salivary gland tumors, including malignant mucoepidermoid carcinoma. This mutation results in an aberrant fusion of the MAML2 gene with the MECT gene (the cAMP response element-binding protein, or CREB, regulator), thereby dramatically altering important signaling mechanisms including the Notch and CREB pathways (Nat. Genet. 2003; EMBO J.2005). More recently, we revealed an essential regulatory role for another member of the MAML family, the Maml1 gene, in myogenesis (Genes Dev. 2006). This study suggested that a mis-regulation of Maml1 gene function might contribute to the pathology of muscle myopathies. Combined, these studies point toward diverse cellular roles for the MAML family of proteins in humans, and reveal that they function with Notch signaling, but also with other signaling pathways.
Currently, we are conducting research to investigate the roles of the MAML family of transcriptional co-activators in normal development and in epithelial cancers, particularly focusing on delineating their interactions with the Notch signaling pathway and other signaling pathways. Our specific research goals include: (1) Elucidating the transcriptional regulation and biological consequences of Notch signaling and its crosstalk with other signaling pathways. (2) Deciphering the roles of Notch signaling and the MAML family in cancer pathogenesis. We are aiming to understand how viral oncoproteins, including HPV E6, target the Notch signaling pathway, resulting in cellular transformation. (3). Studying potential Notch-independent functions for the MAML co-activators in cellular differentiation processes, including myogenesis and adipogenesis. We are pursuing these studies using a combination of molecular, cellular, biochemical, and genetic strategies in mammalian tissue culture and gene-targeted mouse model systems.
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