Inflammatory bowel disease (IBD) is a risk factor for the development of colorectal cancer (CRC) for which mutation to p53 is an early event leading to dysplasia. Interestingly, P2RY6 mRNA increases in both pathologies. In this study, we investigated if p53 and p53(R273H) mutant, commonly found in CRC and IBD, were involved in the transcriptional regulation of P2RY6. First, the P2RY6 promoter was defined as a region corresponding to similar to 1600 to +273 nucleotides relative to the putative TATA-less transcriptional starting site found at position 73,264,505 of NCBI reference sequence NC_000010.11. We cloned this promoter region along with 50-deletion constructs in the pGL4.10[luc2] vector for luciferase assays to delineate the minimal promoter region. We observed that p53 (wt) and p53(R273H) differentially regulated the transcription of the P2RY6 gene. In fact, increasing quantity of p53(R273H) enhanced the capacity of p53 (wt) to stimulate the transactivation of the P2RY6 promoter but this cooperative effect was lost when p53(R273H) was present in a ratio of 3:1. In accordance with the luciferase assays, ChIP analysis revealed that endogenous p53 (wt) was significantly associated with the P2RY6 proximal promoter, whereas the interaction of the p53(R273H) with the P2RY6 promoter was not significant. Although further studies are required to fully elucidate the molecular determinant controlling P2Y(6) expression in diseases, we propose, for the first time, a molecular mechanism involving a collaboration between p53 (wt) and p53(R273H) to regulate the expression of this receptor. (C) 2020 Elsevier Inc. All rights reserved.