A novel, non-apoptotic role for Scythe/BAT3: a functional switch between the pro- and anti-proliferative roles of p21 during the cell cycle.


Autoria(s): Yong, ST; Wang, XF
Contribuinte(s)

Wang, Xiao-Fan

Data(s)

2012

Resumo

BACKGROUND: Scythe/BAT3 is a member of the BAG protein family whose role in apoptosis has been extensively studied. However, since the developmental defects observed in Bat3-null mouse embryos cannot be explained solely by defects in apoptosis, we investigated whether BAT3 is also involved in cell-cycle progression. METHODS/PRINCIPAL FINDINGS: Using a stable-inducible Bat3-knockdown cellular system, we demonstrated that reduced BAT3 protein level causes a delay in both G1/S transition and G2/M progression. Concurrent with these changes in cell-cycle progression, we observed a reduction in the turnover and phosphorylation of the CDK inhibitor p21, which is best known as an inhibitor of DNA replication; however, phosphorylated p21 has also been shown to promote G2/M progression. Our findings indicate that in Bat3-knockdown cells, p21 continues to be synthesized during cell-cycle phases that do not normally require p21, resulting in p21 protein accumulation and a subsequent delay in cell-cycle progression. Finally, we showed that BAT3 co-localizes with p21 during the cell cycle and is required for the translocation of p21 from the cytoplasm to the nucleus during the G1/S transition and G2/M progression. CONCLUSION: Our study reveals a novel, non-apoptotic role for BAT3 in cell-cycle regulation. By maintaining a low p21 protein level during the G1/S transition, BAT3 counteracts the inhibitory effect of p21 on DNA replication and thus enables the cells to progress from G1 to S phase. Conversely, during G2/M progression, BAT3 facilitates p21 phosphorylation by cyclin A/Cdk2, an event required for G2/M progression. BAT3 modulates these pro- and anti-proliferative roles of p21 at least in part by regulating cyclin A abundance, as well as p21 translocation between the cytoplasm and the nucleus to ensure that it functions in the appropriate intracellular compartment during each phase of the cell cycle.

Dissertation

Identificador

http://www.ncbi.nlm.nih.gov/pubmed/22761665

PONE-D-11-22003

PLoS One, 2012, 7 (6), pp. e38085 - ?

http://hdl.handle.net/10161/4958

1932-6203

Relação

PLoS One

10.1371/journal.pone.0038085

Tipo

Journal Article

Cobertura

United States

Formato

e38085 - ?

Idioma(s)

ENG

Palavras-Chave #Apoptosis #Blotting, Western #Bone Neoplasms #Cell Cycle #Cell Proliferation #Cyclin-Dependent Kinase Inhibitor p21 #DNA Replication #Flow Cytometry #Fluorescent Antibody Technique #Humans #Molecular Chaperones #Osteosarcoma #Phosphorylation #RNA, Small Interfering #Tumor Cells, Cultured