FIH-1 engages novel binding partners to positively influence epithelial proliferation via p63.

ABSTRACT: Whereas much is known about the genes regulated by ?Np63? in keratinocytes, how ?Np63? is regulated is less clear. During studies with the hydroxylase, factor inhibiting hypoxia-inducible factor 1 (FIH-1), we observed increases in epidermal ?Np63? expression along with proliferative capacity in a conditional FIH-1 transgenic mouse. Conversely, loss of FIH-1 in vivo and in vitro attenuated ?Np63? expression. To elucidate the FIH-1/p63 relationship, BioID proteomics assays identified FIH-1 binding partners that had the potential to regulate p63 expression. FIH-1 interacts with two previously unknown partners, Plectin1 and signal transducer and activator of transcription 1 (STAT1) leading to the regulation of ?Np63? expression. Two known interactors of FIH-1, apoptosis-stimulating of P53 protein 2 (ASPP2) and histone deacetylase 1 (HDAC1), were also identified. Knockdown of ASPP2 upregulated ?Np63? and reversed the decrease in ?Np63? by FIH-1 depletion. Additionally, FIH-1 regulates growth arrest and DNA damage-45 alpha (GADD45?), a negative regulator of ?Np63? by interacting with HDAC1. GADD45? knockdown rescued reduction in ?Np63? by FIH-1 depletion. Collectively, our data reveal that FIH-1 positively regulates ?Np63? in keratinocytes via variety of signaling partners: (a) Plectin1/STAT1, (b) ASPP2, and (c) HDAC1/GADD45? signaling pathways.

SUBMITTER: Kaplan N 

PROVIDER: S-EPMC6956705 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature