Abstract
P-glycoprotein (Pgp), encoded by the multidrug resistance 1 (MDR1) gene, is an efflux transporter and plays an important role in pharmacokinetics. In this study, we demonstrated that the pokemon promoter activity, the pokemon mRNA and protein expression can be significantly inhibited by Pgp. Chromatin immunoprecipitation assay showed that Pgp can bind the pokemon prompter to repress pokemon transcription activity. Furthermore, Pgp regulated pokemon transcription activity through expression of p53 as seen by use of p53 siRNA transfected MCF-7 cells or p53 mutated MDA-MB-231 cells. Moreover, p53 was detected to bind with Pgp in vivo using immunoprecipitation assay. Taken together, we conclude that Pgp can regulate the expression of pokemon through the presence of p53, suggesting that Pgp is a potent regulator and may offer an effective novel target for cancer therapy.
Highlights
Multidrug resistance (MDR) plays an important role in chemotherapy treatment, but it is still under investigation whether it is the main one
The function of Pgp as a pump to extrude anticancer drugs from cancer cells has proven the significant role of Pgp in drug pharmacokinetics, and data from mdr knockout transgenic mice strongly support the role of multidrug resistance 1 (MDR1) in drug absorption, disposition, elimination, and detoxification pathways [5,6]
We initially found that in the MCF-7/ADR cell line, pokemon mRNA expression level was lower than that in MCF-7 cell line (Figure 1a, top and bottom)
Summary
Multidrug resistance (MDR) plays an important role in chemotherapy treatment, but it is still under investigation whether it is the main one. P-glycoprotein (Pgp) is a member of ATP-binding cassette transporters that is often over-expressed in drug-resistant cancer cells. It is a 170 kD protein and is encoded by the human MDR1 (ABCB1) gene [2]. Pokemon functionally acts as a transcription factor, which represses the tumor suppressor ARF gene by binding to its promoter region, potentially leading indirectly to p53 inactivation [8]. While dispensable for viability, in response to genotoxic stress, p53 acts as an "emergency brake" inducing either arrest or apoptosis, protecting the genome from accumulating excess mutations Consistent with this notion, cells lacking p53 showed to be more genetically unstable and more prone to tumors [18]. We show that Pgp can down-regulate pokemon expression level through the presence of p53, indicating a function of Pgp in tumor therapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
