CUL-4A is critical for early embryonic development

Binghui Li, Joseph C. Ruiz, Kristin Chun

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Ubiquitin-mediated degradation targets cell cycle regulators for proteolysis. Much of the ubiquitin pathway's substrate specificity is conferred by E3 ubiquitin ligases, and cullins are core components of some E3s. CUL-4A encodes one of six mammalian cullins and is amplified and/or overexpressed in breast cancer, which suggests a role in regulating cell cycle progression. To examine CUL-4A's physiologic function, we generated a CUL-4A deletion mutation in mice. No viable CUL-4A-/- pups and no homozygous mutant embryos as early as 7.5 days postcoitum (dpc) were recovered. However, CUL-4A-/- blastocysts are viable, hatch, form an inner cell mass and trophectoderm, and implant (roughly 4.5 dpc), indicating that CUL-4A-/- embryos die between 4.5 and 7.5 dpc. Despite 87% similarity between the Cul-4A and Cul-4B cullins, the CUL-4A-/- lethal phenotype indicates that CUL-4A has one or more distinct function(s). Surprisingly, 44% fewer heterozygous pups were recovered than expected by Mendelian genetics, indicating that many heterozygous embryos also die during gestation due to haploinsufficiency. Taken together, our findings indicate that appropriate CUL-4A expression is critical for early embryonic development.

Original languageEnglish
Pages (from-to)4997-5005
Number of pages9
JournalMolecular and Cellular Biology
Volume22
Issue number14
DOIs
StatePublished - 2002

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Cullin Proteins
Embryonic Development
Embryonic Structures
Ubiquitin
Cell Cycle
Haploinsufficiency
Ubiquitin-Protein Ligases
Sequence Deletion
Blastocyst
Substrate Specificity
Proteolysis
Breast Neoplasms
Phenotype
Pregnancy

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

CUL-4A is critical for early embryonic development. / Li, Binghui; Ruiz, Joseph C.; Chun, Kristin.

In: Molecular and Cellular Biology, Vol. 22, No. 14, 2002, p. 4997-5005.

Research output: Contribution to journalArticle

Li, Binghui ; Ruiz, Joseph C. ; Chun, Kristin. / CUL-4A is critical for early embryonic development. In: Molecular and Cellular Biology. 2002 ; Vol. 22, No. 14. pp. 4997-5005.
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