| First Author | Kaplan N | Year | 2020 |
| Journal | FASEB J | Volume | 34 |
| Issue | 1 | Pages | 525-539 |
| PubMed ID | 31914679 | Mgi Jnum | J:299491 |
| Mgi Id | MGI:6491780 | Doi | 10.1096/fj.201901512R |
| Citation | Kaplan N, et al. (2020) FIH-1 engages novel binding partners to positively influence epithelial proliferation via p63. FASEB J 34(1):525-539 |
| abstractText | Whereas much is known about the genes regulated by DeltaNp63alpha in keratinocytes, how DeltaNp63alpha is regulated is less clear. During studies with the hydroxylase, factor inhibiting hypoxia-inducible factor 1 (FIH-1), we observed increases in epidermal DeltaNp63alpha expression along with proliferative capacity in a conditional FIH-1 transgenic mouse. Conversely, loss of FIH-1 in vivo and in vitro attenuated DeltaNp63alpha 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 DeltaNp63alpha 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 DeltaNp63alpha and reversed the decrease in DeltaNp63alpha by FIH-1 depletion. Additionally, FIH-1 regulates growth arrest and DNA damage-45 alpha (GADD45alpha), a negative regulator of DeltaNp63alpha by interacting with HDAC1. GADD45alpha knockdown rescued reduction in DeltaNp63alpha by FIH-1 depletion. Collectively, our data reveal that FIH-1 positively regulates DeltaNp63alpha in keratinocytes via variety of signaling partners: (a) Plectin1/STAT1, (b) ASPP2, and (c) HDAC1/GADD45alpha signaling pathways. |
