CUL-4A stimulates ubiquitylation and degradation of the HOXA9 homeodomain protein

Yue Zhang, Giovanni Morrone, Jianxuan Zhang, Xiaoai Chen, Xiaoling Lu, Liang Ma, Malcolm Moore, Pengbo Zhou

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

The HOXA9 homeodomain protein is a key regulator of hematopoiesis and embryonic development. HOXA9 is expressed in primitive hematopoietic cells, and its prompt downregulation is associated with myelocytic maturation. Although transcriptional inactivation of HOXA9 during hematopoietic differentiation has been established, little is known about the biochemical mechanisms underlying the subsequent removal of HOXA9 protein. Here we report that the CUL-4A ubiquitylation machinery controls the stability of HOXA9 by promoting its ubiquitylation and proteasome-dependent degradation. The homeodomain of HOXA9 is responsible for CUL-4A-mediated degradation. Interfering CUL-4A biosynthesis by ectopic expression or by RNA-mediated interference resulted in alterations of the steady-state levels of HOXA9, mirrored by impairment of the ability of 32D myeloid progenitor cells to undergo proper terminal differentiation into granulocytes. These results revealed a novel regulatory mechanism of hematopoiesis by ubiquitin-dependent proteolysis.

Original languageEnglish
Pages (from-to)6057-6067
Number of pages11
JournalEMBO Journal
Volume22
Issue number22
DOIs
StatePublished - Nov 17 2003

Keywords

  • CUL-4A
  • HOXA9
  • Hematopoiesis
  • Homeodomain
  • Proteolysis
  • RNAi
  • Ubiquitin

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