Altered sumoylation of p63α contributes to the split-hand/foot malformation phenotype

Yi Ping Huang, Guojun Wu, Zhongmin Guo, Motonobu Osada, Tanya Fomenkov, Hannah Lui Park, Barry Trink, David Sidransky, Alexey Fomenkov, Edward A. Ratovitski

Research output: Contribution to journalArticle

Abstract

p63 mutations have been identified in several developmental abnormalities, including split-hand/foot malformation (SHFM). In this study, we demonstrate that the C-terminal domain of p63α associates with the E2 ubiquitin conjugating enzyme, Ubc9. A p63α mutation, Q634X, which naturally occurs in SHFM modulated the interaction of p63α with Ubc9 in yeast genetic assay. Furthermore, Ubc9 catalyzed the conjugation of p63α with small ubiquitin modifier-1 (SUMO-1), which covalently modified p63α in vitro and in vivo at two positions (K549E and K637E), each situated in a SUMO-1 modification consensus site (φKXD/E). In addition, p63α mutations (K549E and K637E) abolished sumoylation of p63α, dramatically activated transactivation properties of TAp63α, and inhibited the dominant-negative effect of ΔNp63α. These p63α mutations also affected the transcriptional regulation of gene targets involved in bone and tooth development (e.g., RUNX2 and MINT) and therefore might contribute to the molecular mechanisms underlying the SHFM phenotype.

Original languageEnglish (US)
Pages (from-to)1587-1596
Number of pages10
JournalCell Cycle
Volume3
Issue number12
DOIs
StatePublished - Dec 2004

Keywords

  • MINT
  • RUNX2
  • SHFM
  • SUMO-1
  • Split-hand/foot malformation
  • Ubiquitin
  • p63

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Huang, Y. P., Wu, G., Guo, Z., Osada, M., Fomenkov, T., Park, H. L., Trink, B., Sidransky, D., Fomenkov, A., & Ratovitski, E. A. (2004). Altered sumoylation of p63α contributes to the split-hand/foot malformation phenotype. Cell Cycle, 3(12), 1587-1596. https://doi.org/10.4161/cc.3.12.1290