This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cadherins are a class of adhesion proteins required for tissue integrity. They are transmembrane proteins that form homodimers with cadherins on adjacent cells and attach either directly or indirectly to the cytoskeleton. E-cadherin is the most thoroughly studied cadherin due to its role in epithelial tissue maintenance. Most human cancers arise in epithelial tissues, and, during tumor progression, tumor cells may begin expressing N-cadherin inappropriately. N-cadherin is named for its role in neurite outgrowth, is found in more mesenchymal tissues, and tumor cells that begin expressing N-cadherin become more motile and invasive. The N-cadherin gene has only recently become the subject of study and promoter characterization in order to understand the regulation of transcription has been limited. The misexpression of N-cadherin in cancer cells appears to be very similar to the increase in N-cadherin expression that occurs during the normal developmental epithelial-to-mesenchymal transition (EMT), suggesting that insight into this metastatic transition can be gleaned from studies in EMT model cell culture systems. The overall goal of this research is to identify specific transcription factor binding sites, transcription factors, and epigenetic promoter modifications involved in regulating transcription of the human N-cadherin gene.
Specific Aim 1 is to evaluate a putative repressor site between -462bp and -1896bp of the N-cadherin promoter in detail using luciferase reporters.
Specific Aim 2 is to evaluate the proposed trancriptional role of a LEF-1 consensus binding site 60bp 3'of the first exon also using luciferase reporters.
Specific Aim 3 involves using chromatin immuno-precipitation (ChIP) to detect in vivo binding of transcription factors including AP-1, LEF-1, any identified repressor, and potential epigenetic modifications including methylation. If ChIP assays indicate that AP-1, LEF-1 or other relevant transcription factors are binding to N-cadherin promoter fragments, Specific Aim 4 is to evaluate expression of N-cadherin promoter fragment-luciferase reporters in EMT model cell culture systems in which components of the EMT inducing signaling pathways can be interrupted.
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