CUL-4A Is Critical for Early Embryonic Development
| Autor: | Binghui Li, Kristin T. Chun, Joseph C. Ruiz |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Heterozygote
Mutant Breast Neoplasms Gestational Age Embryonic and Fetal Development Mice Ubiquitin Pregnancy Mammalian Genetic Models with Minimal or Complex Phenotypes medicine Animals Humans Inner cell mass Blastocyst Fetal Death Molecular Biology Mice Knockout Base Sequence biology Homozygote Embryogenesis Gene Expression Regulation Developmental Embryo DNA Cell Biology Cell cycle Cullin Proteins Molecular biology Neoplasm Proteins medicine.anatomical_structure Gene Targeting embryonic structures biology.protein Female Haploinsufficiency |
| Zdroj: | Molecular and Cellular Biology. 22:4997-5005 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.22.14.4997-5005.2002 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|