CUL9 mediates the functions of the 3M complex and ubiquitylates survivin to maintain genome integrity.
The Cullin 9 (CUL9) gene encodes a putative E3 ligase that localizes in the cytoplasm. Cul9 null mice develop spontaneous tumors in multiple organs; however, both the cellular and the molecular mechanisms of CUL9 in tumor suppression are currently unknown. We show here that deletion of Cul9 leads to abnormal ... nuclear morphology, increased DNA damage, and aneuploidy. CUL9 knockdown rescues the microtubule and mitosis defects in cells depleted for CUL7 or OBSL1, two genes that are mutated in a mutually exclusive manner in 3M growth retardation syndrome and function in microtubule dynamics. CUL9 promotes the ubiquitylation and degradation of survivin and is inhibited by CUL7. Depletion of CUL7 decreases survivin level, and overexpression of survivin rescues the defects caused by CUL7 depletion. We propose a 3M-CUL9-survivin pathway in maintaining microtubule and genome integrity, normal development, and tumor suppression.
Mesh Terms:
Aneuploidy, Animals, Cell Death, Cullin Proteins, Gene Knockdown Techniques, Genes, Tumor Suppressor, Genomic Instability, HCT116 Cells, Humans, Inhibitor of Apoptosis Proteins, Liver, Mice, Mice, Knockout, Multiprotein Complexes, Polyploidy, Protein Multimerization, Repressor Proteins, Ubiquitination
Aneuploidy, Animals, Cell Death, Cullin Proteins, Gene Knockdown Techniques, Genes, Tumor Suppressor, Genomic Instability, HCT116 Cells, Humans, Inhibitor of Apoptosis Proteins, Liver, Mice, Mice, Knockout, Multiprotein Complexes, Polyploidy, Protein Multimerization, Repressor Proteins, Ubiquitination
Mol. Cell
Date: Jun. 05, 2014
PubMed ID: 24793696
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