PMID- 22745582
OWN - NLM
STAT- MEDLINE
DCOM- 20121107
LR  - 20240318
IS  - 1476-5586 (Electronic)
IS  - 1522-8002 (Print)
IS  - 1476-5586 (Linking)
VI  - 14
IP  - 5
DP  - 2012 May
TI  - Targeting the mTOR-DEPTOR pathway by CRL E3 ubiquitin ligases: therapeutic 
      application.
PG  - 360-7
AB  - The mammalian target of rapamycin (mTOR), an evolutionarily conserved 
      serine/threonine protein kinase, integrates both intracellular and extracellular 
      signals and serves as a central regulator of cell metabolism, growth, 
      proliferation, survival, and autophagy. The mTOR pathway is frequently activated 
      in many human cancers, mainly resulting from alterations in the upstream 
      regulators, such as phosphoinositide 3-kinase (PI3K)/AKT activation, PTEN loss or 
      dysregulation of mTOR-negative regulators (e.g., TSC1/2), leading to uncontrolled 
      proliferation. Thus, inhibiting the PI3K/AKT/mTOR pathways is widely considered 
      as an effective approach for targeted cancer therapy. Recently, we and others 
      found that DEPTOR, a naturally occurring inhibitor of both mTORC1 and mTORC2, was 
      degraded by SCF (Skp1-Cullin-F box proteins) E3 ubiquitin ligase, the founding 
      member of cullin-RING-ligases (CRLs), resulting in mTOR activation and cell 
      proliferation. In addition to DEPTOR, previous studies have demonstrated that 
      several other negative regulators of mTOR pathway are also substrates of CRL/SCF 
      E3s. Thus, targeting CRL/SCF E3s is expected to cause the accumulation of these 
      mTOR signal inhibitors to effectively block the mTOR pathway. In this review, we 
      will discuss mTOR signaling pathway, how DEPTOR regulates mTOR/AKT axis, thus 
      acting as a tumor suppressor or oncogene in some cases, how DEPTOR is 
      ubiquitinated and degraded by SCF(beta-TrCP) E3, and how MLN4924, a small-molecule 
      indirect inhibitor of CRL/SCF E3 ligases through blocking cullin neddylation, 
      might be useful as a novel approach of mTOR pathway targeting for cancer therapy.
FAU - Zhao, Yongchao
AU  - Zhao Y
AD  - Division of Radiation and Cancer Biology, Department of Radiation Oncology, 
      University of Michigan, Ann Arbor, MI 48109, USA.
FAU - Sun, Yi
AU  - Sun Y
LA  - eng
GR  - R01 CA118762/CA/NCI NIH HHS/United States
GR  - R01 CA156744/CA/NCI NIH HHS/United States
GR  - CA118762/CA/NCI NIH HHS/United States
GR  - CA156744/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Review
PL  - United States
TA  - Neoplasia
JT  - Neoplasia (New York, N.Y.)
JID - 100886622
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases)
RN  - EC 2.7.1.1 (DEPTOR protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Neoplasms/drug therapy/metabolism
MH  - Protein Kinase Inhibitors/pharmacology/therapeutic use
MH  - SKP Cullin F-Box Protein Ligases/antagonists & inhibitors/*metabolism
MH  - *Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Ubiquitination
PMC - PMC3384423
EDAT- 2012/06/30 06:00
MHDA- 2012/11/08 06:00
PMCR- 2012/05/01
CRDT- 2012/06/30 06:00
PHST- 2012/03/18 00:00 [received]
PHST- 2012/04/10 00:00 [revised]
PHST- 2012/04/12 00:00 [accepted]
PHST- 2012/06/30 06:00 [entrez]
PHST- 2012/06/30 06:00 [pubmed]
PHST- 2012/11/08 06:00 [medline]
PHST- 2012/05/01 00:00 [pmc-release]
AID - 12532 [pii]
AID - 10.1593/neo.12532 [doi]
PST - ppublish
SO  - Neoplasia. 2012 May;14(5):360-7. doi: 10.1593/neo.12532.