USP7 and Daxx regulate mitosis progression and taxane sensitivity by affecting stability of Aurora-A kinase. (Cell Death Differ 2013 May;20(5):721-31.)

報告日期: 2014/05/02
報告時間: 3:10/4:00
報告學生: 王毅昌(以英文報告)
講評老師: 洪良宜
附件下載: 下載[1402-1396958498-1.pdf] 

USP7 and Daxx regulate mitosis progression and taxane sensitivity

by affecting stability of Aurora-A kinase

S Giovinazzi, VM Morozov, MK Summers, WC Reinholdand AM Ishov

 

Cell Death and Differentiation 2013 May;20(5):721-31.

 

Speaker: Yi-Chang Wang                                        Date: 2014.05.02.

Commentator: Dr. Liang-Yi Hung                                  Place: Room 602

 

Abstarct:

Taxane, a widely used chemotherapy agent, can inhibit the depolymerization of microtubules in mitosis and interphase, leads to mitotic arrest and eventually apoptotic cell death. However, resistance to taxane is frequently observed, and becomes a major obstacle to improving the survival of cancer patients. Besides overexpression of tubulin isotype, other mechanisms such as cell cycle-dependent resistance have also been reported to involve in taxane resistance. In author’s previous study, he found that death domain-associated protein (Daxx), which participated in many nuclear processes including transcription and cell cycle regulation, may be important to the acquirement of taxane resistance. In order to elucidate the detail mechanism of Daxx-based taxane resistance, the author used mass spectrometry to identify Daxx-interacting proteins. He found USP7, a deubiquitylating enzyme, which can remove the ubiquitin signals from substrate proteins and rescue ubiquitinated proteins from degradation, can interact with Daxx in mitosis. He also found that knockdown of USP7 stabilizes cyclin B and causes the accumulation of cells in prometa/metaphases in a p53-independent manner. Moreover, USP7 depletion destabilizes mitotic E3 ligase CHFR (checkpoint with forkhead and Ring-finger) and causes mitotic defects by increasing CHFR substrate Aurora-A kinase, which controls bipolar spindle formation, centrosome maturation and separation. USP7 mRNA expression level analyzed in 60 human cancer cell lines also show that cell lines with low expression of USP7 are significantly less responsive to taxane than those with high USP7. In the end, the author demonstrates that combine treatment of tanxan with small molecule inhibitor of Aurora-A, MLN8054, can overcome USP7-mediated taxane resistance. Thus, in this study, the author proposes a new role for USP7 and Daxx in mitotic progression and taxane resistance, and can be served as novel markers for taxane response.

References:

  1. Lindsay CR, Scholz A, Morozov VM, Ishov AM. Daxx shortens mitotic arrest caused by paclitaxel. Cell Cycle 2007; 6: 1200–1204.
  2. Giovinazzi S, Lindsay CR, Morozov VM, Escobar-Cabrera E, Summers MK, Han HS et al. Regulation of mitosis and taxane response by Daxx and Rassf1. Oncogene 2012; 31: 13–26.