We hypothesize that p63 functions through physical and functional interaction with other cellular proteins contributing in regulation of cell proliferation, differentiation and pathogenesis of skin-related disorders. We recently demonstrated that p63alpha associates with RNA processing molecular machinery through binding to ABBP1 and SCAF4 proteins that leads to regulation of the fibroblast growth factor receptor (FGFR)-2 RNA splicing towards epithelial-specific FGFR-2 isoform. We suggest that this post-transcriptional regulatory mechanism contributes to pathogenesis of AEC syndrome, which might represent dysregulation of epithelial/mesenchymal differentiation program. ? ? To support our hypothesis, we will perform the following Specific Aims: (1) to analyze the physical association and subcellular colocalization between p63alpha and RNA splicing proteins (ABBP1 and SCAF4/rA4) in keratinocytes and primary epithelial/skin cultures (epidermal dysplasia); (2) to study the functional effect of p63/ABBP1/SCAF4 complexes on FGFR-2 splicing in ectodermal dysplasia; (3) to evaluate the effect of p63/ABBP1/SCAF4 complexes on gene target expression in keratinocytes and primary epithelial cultures. ? ? We will use modern molecular biology approaches of functional genomics and proteomics including protein-protein interaction analysis and DNA microarray analysis/promoter analysis. ? ?
| Huang, Yi-Ping; Kim, Yuriy; Li, Zhaobo et al. (2005) AEC-associated p63 mutations lead to alternative splicing/protein stabilization of p63 and modulation of Notch signaling. Cell Cycle 4:1440-7 |
| Huang, Yi-Ping; Wu, Guojun; Guo, Zhongmin et al. (2004) Altered sumoylation of p63alpha contributes to the split-hand/foot malformation phenotype. Cell Cycle 3:1587-96 |
| Fomenkov, Alexey; Zangen, Rachel; Huang, Yi-Ping et al. (2004) RACK1 and stratifin target DeltaNp63alpha for a proteasome degradation in head and neck squamous cell carcinoma cells upon DNA damage. Cell Cycle 3:1285-95 |
