Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex
| العنوان: | Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex |
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| المؤلفون: | Shigeo Ohno, Hisashi Hirano, Mariko Ide, Kazunari Yamashita, Atsushi Suzuki, Kana T. Furukawa |
| المصدر: | Molecular Biology of the Cell |
| بيانات النشر: | The American Society for Cell Biology, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Ubiquitin-Protein Ligases, chemical and pharmacologic phenomena, Cell Count, Protein Serine-Threonine Kinases, Cell Line, Madin Darby Canine Kidney Cells, DDB1, Dogs, Ubiquitin, Cell polarity, Animals, Drosophila Proteins, Humans, Molecular Biology, Neurofibromin 2, biology, Cell growth, Tumor Suppressor Proteins, Cell Cycle, Cell Polarity, Cell Biology, Articles, G1 Phase Cell Cycle Checkpoints, Ubiquitin ligase, Cell biology, DNA-Binding Proteins, HEK293 Cells, biology.protein, Phosphorylation, CUL4A, Carrier Proteins, G1 phase, HeLa Cells |
| الوصف: | Lgl is a conserved tumor suppressor suggested to be involved in cell polarity regulation and suppression of cell proliferation. Lgl inhibits formation of the VprBP-DDB1-Cul4A-Roc1 ubiquitin E3 ligase complex, which is implicated in cell cycle progression, by promoting formation of the Lgl-VprBP-DDB1 complex to prevent overproliferation. Lethal giant larvae (Lgl) is an evolutionarily conserved tumor suppressor whose loss of function causes disrupted epithelial architecture with enhanced cell proliferation and defects in cell polarity. A role for Lgl in the establishment and maintenance of cell polarity via suppression of the PAR-aPKC polarity complex is established; however, the mechanism by which Lgl regulates cell proliferation is not fully understood. Here we show that depletion of Lgl1 and Lgl2 in MDCK epithelial cells results in overproliferation and overproduction of Lgl2 causes G1 arrest. We also show that Lgl associates with the VprBP-DDB1 complex independently of the PAR-aPKC complex and prevents the VprBP-DDB1 subunits from binding to Cul4A, a central component of the CRL4 [VprBP] ubiquitin E3 ligase complex implicated in G1- to S-phase progression. Consistently, depletion of VprBP or Cul4 rescues the overproliferation of Lgl-depleted cells. In addition, the affinity between Lgl2 and the VprBP-DDB1 complex increases at high cell density. Further, aPKC-mediated phosphorylation of Lgl2 negatively regulates the interaction between Lgl2 and VprBP-DDB1 complex. These results suggest a mechanism protecting overproliferation of epithelial cells in which Lgl plays a critical role by inhibiting formation of the CRL4 [VprBP] complex, resulting in G1 arrest. |
| اللغة: | English |
| تدمد: | 1939-4586 1059-1524 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::899b548bed7ce5dec9848ab960d96fd6 http://europepmc.org/articles/PMC4571298 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....899b548bed7ce5dec9848ab960d96fd6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19394586 10591524 |
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