PMID- 15021888
OWN - NLM
STAT- MEDLINE
DCOM- 20040413
LR  - 20071114
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 23
IP  - 11
DP  - 2004 Mar 15
TI  - Regulation of apoptosis proteins in cancer cells by ubiquitin.
PG  - 2009-15
AB  - Ubiquitin inhibitors act at many levels to enhance apoptosis signaling. For 
      TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis signaling, there 
      are at least five mechanisms by which apoptosis are regulated by the 
      ubiquitin-proteasome pathway. First, proteasome inhibitors can decrease Fas-like 
      inhibitor protein (FLIP) protein levels in tumors, resulting in increased 
      apoptosis signaling due to increased caspase-8 activation. This appears to 
      involve the ubiquitin ligase TNF receptor activation factor-2 (TRAF2) and acts 
      indirectly by causing cell-cycle arrest at a stage where there is high 
      degradation of the FLIP-TRAF2 complex. Second, the regulation of the proapoptotic 
      Bcl-2 family member BAX occurs indirectly. Apoptosis signaling and caspase 
      activation results in a confirmation change in the normally monomeric BAX, which 
      exposes the BH3 domain of BAX, leading to dimerization and resistance to 
      ubiquitin degradation. BAX then translocates into the mitochondria, resulting in 
      the release of proapoptotic mitochondrial factors such as cytochrome c and second 
      mitochondria-derived activator of caspase (SMAC). This results in the activation 
      of caspase-9 and formation of the apoptosome and efficient apoptosis signaling. A 
      third mechanism of the regulation of TRAIL signaling in the ubiquitin-proteasome 
      pathway is mediated by the inhibitor of apoptosis proteins (IAP) E3 ligases. 
      These IAPs can directly bind to caspases but also can act as ubiquitin ligases 
      for caspases, resulting in the degradation of these caspases. IAP binding to 
      caspases can be inhibited by SMAC, which exhibits a caspase-9 homology domain. 
      The fourth mechanism for apoptosis activation by proteasome inhibitors is through 
      the stabilization of the inhibitor of the kappaB (IkappaB)/NF-kappaB complex and 
      prevention of nuclear translocation of the antiapoptosis transcription factor 
      NF-kappaB. During TRAIL-DR4, DR5 signaling, this pathway is activated by 
      interactions of activated Fas-associated death domain with activated 
      receptor-interacting protein (RIP), which in turn activates NF-kappaB-inducing 
      kinase and phosphorylates IkappaB. Therefore, the inhibition of IkappaB 
      degradation blocks this RIP-mediated antiapoptosis signaling event. Last, p53 
      protein levels, and susceptibility to apoptosis, can be deregulated by the human 
      homolog Hdm2 (Mdm2) E3 ligase. This process is inhibited by p53 phosphorylation 
      and by sequestration of Mdm2 by ARF. Better mechanisms to inhibit the 
      ubiquitin-proteasome pathway targeted at the ubiquitin-proteasome degradation 
      process itself, or more specifically at the E3 ligases known to modulate and 
      downregulate proapoptosis pathways will lead to the enhancement of TRAIL 
      apoptosis signaling and better cancer therapeutic outcomes act through this 
      pathway.
FAU - Zhang, Huang-Ge
AU  - Zhang HG
AD  - Department of Medicine, Division of Clinical Immunology and Rheumatology, The 
      University of Alabama at Birmingham, Birmingham, AL 35294, USA.
FAU - Wang, Jianhua
AU  - Wang J
FAU - Yang, Xinwen
AU  - Yang X
FAU - Hsu, Hui-Chen
AU  - Hsu HC
FAU - Mountz, John D
AU  - Mountz JD
LA  - eng
GR  - CA 20408/CA/NCI NIH HHS/United States
GR  - R01 AG 11653/AG/NIA NIH HHS/United States
GR  - R01 AI 42900/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Proteins)
RN  - 0 (Ubiquitin)
SB  - IM
MH  - Animals
MH  - *Apoptosis
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Models, Biological
MH  - Neoplasms/*metabolism/*pathology
MH  - Proteins/genetics/*metabolism
MH  - Ubiquitin/*metabolism
RF  - 57
EDAT- 2004/03/17 05:00
MHDA- 2004/04/14 05:00
CRDT- 2004/03/17 05:00
PHST- 2004/03/17 05:00 [pubmed]
PHST- 2004/04/14 05:00 [medline]
PHST- 2004/03/17 05:00 [entrez]
AID - 1207373 [pii]
AID - 10.1038/sj.onc.1207373 [doi]
PST - ppublish
SO  - Oncogene. 2004 Mar 15;23(11):2009-15. doi: 10.1038/sj.onc.1207373.