Downregulation of PERP is associated with the aggressive, monosomy 3-type of uveal melanoma (UM), the most common primary intraocular tumour in adults, and increased PERP expression has a pro-apoptotic effect in UM cells.
The aim of this study was to investigate the effect of increased PERP expression on its own upstream transcriptional regulator, p53.
The effect of increased PERP expression described above was found in transiently transfected cell populations where, on average, the transfection efficiency was 13%.
In addition, most of the TAp63 downstream apoptotic genes, including BAX, NOXA, PUMA and PERP, increased over time (Additional file 1: Figure S4A and 4D).
The major components of the desmosome complex, DSC2, DSC3, and Perp, are increased approximately 8-, 40- and 5- fold, respectively, in Cr VI) transformed cells.
Interestingly, similar to the PDCD2-deficient MEFs, expression of RNAs for the p53 targets p21, Mdm2 and PERP was increased in PDCD2-deficient ESCs (Fig. 2C).
As p53Ser20P is known to interfere with p53 binding to MDM2, it is possible that this modification may contribute to the PERP-related increased p53 accumulation.
The initial findings that elevated PERP expression resulted in increased p53 protein levels in MEL202 cells suggested a role for PERP in the positive feedback regulation of its own transcriptional regulator, with potential implications for the regulation of p53 and the vast array of p53-targets involved in the tight control of cell cycle arrest and apoptosis.
Decreased c-myc in MCF10A also agrees with an increase in PERP as c-myc protein represses expression of PERP [ 41].
Moreover, Perp loss correlates with increased rates of local relapse in human head and neck squamous cell carcinoma patients (personal communication, Quynh-Thu Le, M.D).
Several direct targets of p53 were increased in Cr VI) transformed cells, including CYFIP2, Perp, and RNF144B, which were known to mediate p53-dependent apoptosis.
