title: FBXW7 is involved in Aurora B degradation.
abstract: FBXW7, a component of E3 ubiquitin ligase, plays an important role in mitotic checkpoint, but its role remains unclear. Aurora B is a mitotic checkpoint kinase that plays a pivotal role in mitosis by ensuring correct chromosome segregation and normal progression through mitosis. Whether Aurora B and FBXW7 are coordinately regulated during mitosis is not known. Here, we show that FBXW7 is a negative regulator for Aurora B. Ectopic expression of FBXW7 can suppress the expression of Aurora B. Accordingly, FBXW7 deficiency leads to Aurora B elevation. Mechanistic studies show that all FBXW7 isoforms are negative regulators of Aurora B expression through ubiquitination-mediated protein degradation. Aurora B interacts with R465 and R505 residues of WD 40 domain of FBXW7. Significantly, inverse correlation between FBXW7 and Aurora B elevation is translated into the deregulation of mitosis. FBWX7 expression mitigates Aurora B-mediated cell growth and mitotic deregulation. In addition, FBXW7 reduces the percentage of multinucleated cells caused by Aurora B overexpression. These data suggest that FBXW7 is an important negative regulator of Aurora B, and that the loss or mutation of FBXW7 as seen in many types of cancer could lead to an abnormal elevation of Aurora B and result in deregulated mitosis, which accelerates cancer cell growth.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Chieh-Lin
authors.initials: CL
authors.lastname: Teng
authors.forename: Yun-Chi
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Liem
authors.initials: L
authors.lastname: Phan
authors.forename: Jihyun
authors.initials: J
authors.lastname: Shin
authors.forename: Chris
authors.initials: C
authors.lastname: Gully
authors.forename: Guermarie
authors.initials: G
authors.lastname: Velazquez-Torres
authors.forename: Stephen
authors.initials: S
authors.lastname: Skerl
authors.forename: Sai-Ching J
authors.initials: SC
authors.lastname: Yeung
authors.forename: Shih-Lan
authors.initials: SL
authors.lastname: Hsu
authors.forename: Mong-Hong
authors.initials: MH
authors.lastname: Lee
mesh_terms: D064107:Aurora Kinase B; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D007976:Leupeptins; D011480:Protease Inhibitors; D020033:Protein Isoforms; D044767:Ubiquitin-Protein Ligases; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde