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

Nihal Kaplan, Ying Dong, Sijia Wang, Wending Yang, Jong Kook Park, Junyi Wang, Elaina Fiolek, Bethany Perez White, Navdeep S. Chandel, Han Peng*, Robert M. Lavker

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Whereas much is known about the genes regulated by ΔNp63α in keratinocytes, how ΔNp63α is regulated is less clear. During studies with the hydroxylase, factor inhibiting hypoxia-inducible factor 1 (FIH-1), we observed increases in epidermal ΔNp63α expression along with proliferative capacity in a conditional FIH-1 transgenic mouse. Conversely, loss of FIH-1 in vivo and in vitro attenuated ΔNp63α 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 ΔNp63α 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 ΔNp63α and reversed the decrease in ΔNp63α by FIH-1 depletion. Additionally, FIH-1 regulates growth arrest and DNA damage-45 alpha (GADD45α), a negative regulator of ΔNp63α by interacting with HDAC1. GADD45α knockdown rescued reduction in ΔNp63α by FIH-1 depletion. Collectively, our data reveal that FIH-1 positively regulates ΔNp63α in keratinocytes via variety of signaling partners: (a) Plectin1/STAT1, (b) ASPP2, and (c) HDAC1/GADD45α signaling pathways.

Original languageEnglish (US)
Pages (from-to)525-539
Number of pages15
JournalFASEB Journal
Volume34
Issue number1
DOIs
StatePublished - Jan 1 2020

Keywords

  • ASPP2
  • GADD45α
  • epidermis
  • limbal and corneal epithelia

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'FIH-1 engages novel binding partners to positively influence epithelial proliferation via p63'. Together they form a unique fingerprint.

  • Cite this