Cargando…
Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex
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-aPK...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571298/ https://www.ncbi.nlm.nih.gov/pubmed/25947136 http://dx.doi.org/10.1091/mbc.E14-10-1462 |
_version_ | 1782390313426354176 |
---|---|
author | Yamashita, Kazunari Ide, Mariko Furukawa, Kana T. Suzuki, Atsushi Hirano, Hisashi Ohno, Shigeo |
author_facet | Yamashita, Kazunari Ide, Mariko Furukawa, Kana T. Suzuki, Atsushi Hirano, Hisashi Ohno, Shigeo |
author_sort | Yamashita, Kazunari |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4571298 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-45712982015-09-29 Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex Yamashita, Kazunari Ide, Mariko Furukawa, Kana T. Suzuki, Atsushi Hirano, Hisashi Ohno, Shigeo Mol Biol Cell Articles 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. The American Society for Cell Biology 2015-07-01 /pmc/articles/PMC4571298/ /pubmed/25947136 http://dx.doi.org/10.1091/mbc.E14-10-1462 Text en © 2015 Yamashita et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Yamashita, Kazunari Ide, Mariko Furukawa, Kana T. Suzuki, Atsushi Hirano, Hisashi Ohno, Shigeo Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex |
title | Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex |
title_full | Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex |
title_fullStr | Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex |
title_full_unstemmed | Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex |
title_short | Tumor suppressor protein Lgl mediates G1 cell cycle arrest at high cell density by forming an Lgl-VprBP-DDB1 complex |
title_sort | tumor suppressor protein lgl mediates g1 cell cycle arrest at high cell density by forming an lgl-vprbp-ddb1 complex |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571298/ https://www.ncbi.nlm.nih.gov/pubmed/25947136 http://dx.doi.org/10.1091/mbc.E14-10-1462 |
work_keys_str_mv | AT yamashitakazunari tumorsuppressorproteinlglmediatesg1cellcyclearrestathighcelldensitybyforminganlglvprbpddb1complex AT idemariko tumorsuppressorproteinlglmediatesg1cellcyclearrestathighcelldensitybyforminganlglvprbpddb1complex AT furukawakanat tumorsuppressorproteinlglmediatesg1cellcyclearrestathighcelldensitybyforminganlglvprbpddb1complex AT suzukiatsushi tumorsuppressorproteinlglmediatesg1cellcyclearrestathighcelldensitybyforminganlglvprbpddb1complex AT hiranohisashi tumorsuppressorproteinlglmediatesg1cellcyclearrestathighcelldensitybyforminganlglvprbpddb1complex AT ohnoshigeo tumorsuppressorproteinlglmediatesg1cellcyclearrestathighcelldensitybyforminganlglvprbpddb1complex |