ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Please note that you are viewing an archived section from 2020 and some content may be unavailable. To unlock all content for 2020, please visit the archives.

Abstract: PO1516

FPC, TFAP2B, and MCM3 Function in a Species-Specific Regulome That Modulates Myc/MYC Expression: Implications for ARPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Harafuji, Naoe, Center for Translational Research, Children’s National Medical Center, Washington, District of Columbia, United States
  • Yang, Chaozhe, Center for Translational Research, Children’s National Medical Center, Washington, District of Columbia, United States
  • Odinakachukwu, Maryanne, Center for Translational Research, Children’s National Medical Center, Washington, District of Columbia, United States
  • Wu, Maoqing, Center for Translational Research, Children’s National Medical Center, Washington, District of Columbia, United States
  • Caldovic, Ljubica, Center for Genetic Medicine Research, Children’s National Medical Center, Washington, District of Columbia, United States
  • Guay-Woodford, Lisa M., Center for Translational Research, Children’s National Medical Center, Washington, District of Columbia, United States
Background

Mutations in PKHD1 cause human ARPKD (MIM 263200), but mouse Pkhd1 mutants have limited or no renal cystic disease. We previously showed that MYC is overexpressed in human ARPKD kidneys but not in mouse Pkhd1 mutant kidneys, and that mouse FPC C-terminal domain (FPC-CTD) activates Myc (ASN 2018). Trudel (2019) has reported that Myc is a central driver in Pkd1-induced pathogenesis. Relevant to the current study, mice express three TFAP2B isoforms while humans express only one, which is most similar to mouse isoform TFAP2B1. Here, we describe a species-specific regulatory framework (regulome) in which FPC-CTD, TFAP2B, and MCM3 regulate Myc/MYC in renal collecting duct (CD) cells.

Methods

Human and mouse CD cell lines, Myc-tagged TFAP2B, Tfap2b1, and Tfap2b2, V5-tagged human and mouse FPC-CTD constructs, and Cys1, Pkhd1 and Myc/MYC promoter constructs were used to perform dual luciferase and co-IP assays.

Results

In mouse cells, TFAP2B1 & 2 positively regulated expression of Pkhd1 and Cys1 while Myc was positively regulated by TFAP2B2 but negatively regulated by TFAP2B1. TFAP2B1 negative regulation of Myc was epistatic over FPC-CTD activation. MCM3, previously identified as a FPC-CTD binding partner, positively regulated Myc promoter activity. Human MYC was activated by FPC-CTD and negatively regulated by TFAP2B.

Conclusion

We show that in both mouse and human, FPC-CTD and TFAP2B regulate Myc/MYC expression. Notably, mouse TFAP2B isoforms differentially regulate Myc expression, while humans lack a MYC activating isoform. Based on our data, we propose a model in which a regulome that includes FPC-CTD, TFAP2B, and MCM3 modulates Myc/MYC expression in CD cells in a species-specific fashion. Species-specific renal phenotypes could be attributable to differences in constituent proteins, isoform diversity, and epistatic interactions within the proposed regulome. We speculate that this model may explain the differential effects of PKHD1/Pkhd1 deficiency on renal cystogenesis and provide initial clues for putative renoprotective mechanisms in Pkhd1 mutant mice.

Funding

  • NIDDK Support