PMID- 21841310
OWN - NLM
STAT- MEDLINE
DCOM- 20111031
LR  - 20211203
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 121
IP  - 9
DP  - 2011 Sep
TI  - Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 
      4E-BP1 translation regulator.
PG  - 3623-34
LID - 46323 [pii]
LID - 10.1172/JCI46323 [doi]
AB  - Merkel cell polyomavirus (MCV) is the recently discovered cause of most Merkel 
      cell carcinomas (MCCs), an aggressive form of nonmelanoma skin cancer. Although 
      MCV is known to integrate into the tumor cell genome and to undergo mutation, the 
      molecular mechanisms used by this virus to cause cancer are unknown. Here, we 
      show that MCV small T (sT) antigen is expressed in most MCC tumors, where it is 
      required for tumor cell growth. Unlike the closely related SV40 sT, MCV sT 
      transformed rodent fibroblasts to anchorage- and contact-independent growth and 
      promoted serum-free proliferation of human cells. These effects did not involve 
      protein phosphatase 2A (PP2A) inhibition. MCV sT was found to act downstream in 
      the mammalian target of rapamycin (mTOR) signaling pathway to preserve eukaryotic 
      translation initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation, 
      resulting in dysregulated cap-dependent translation. MCV sT-associated 4E-BP1 
      serine 65 hyperphosphorylation was resistant to mTOR complex (mTORC1) and mTORC2 
      inhibitors. Steady-state phosphorylation of other downstream Akt-mTOR targets, 
      including S6K and 4E-BP2, was also increased by MCV sT. Expression of a 
      constitutively active 4E-BP1 that could not be phosphorylated antagonized the 
      cell transformation activity of MCV sT. Taken together, these experiments showed 
      that 4E-BP1 inhibition is required for MCV transformation. Thus, MCV sT is an 
      oncoprotein, and its effects on dysregulated cap-dependent translation have 
      clinical implications for the prevention, diagnosis, and treatment of MCV-related 
      cancers.
FAU - Shuda, Masahiro
AU  - Shuda M
AD  - Cancer Virology Program, University of Pittsburgh Cancer Institute, 5117 Centre 
      Avenue, Pittsburgh, Pennsylvania 15213, USA.
FAU - Kwun, Hyun Jin
AU  - Kwun HJ
FAU - Feng, Huichen
AU  - Feng H
FAU - Chang, Yuan
AU  - Chang Y
FAU - Moore, Patrick S
AU  - Moore PS
LA  - eng
GR  - P30 CA047904/CA/NCI NIH HHS/United States
GR  - R01 CA136363/CA/NCI NIH HHS/United States
GR  - R33 CA120726/CA/NCI NIH HHS/United States
GR  - CA136363/CA/NCI NIH HHS/United States
GR  - CA120726/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110815
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antigens, Polyomavirus Transforming)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Phosphoproteins)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Animals
MH  - Antigens, Polyomavirus Transforming/genetics/*metabolism
MH  - Carcinoma, Merkel Cell/*metabolism/pathology/virology
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Cell Proliferation
MH  - Cell Transformation, Neoplastic
MH  - Humans
MH  - Merkel Cells/*virology
MH  - Oncogene Proteins/genetics/*metabolism
MH  - Phosphoproteins/genetics/*metabolism
MH  - Phosphorylation
MH  - Polyomavirus/*metabolism/pathogenicity
MH  - Protein Biosynthesis
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction/physiology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC3163959
EDAT- 2011/08/16 06:00
MHDA- 2011/11/01 06:00
PMCR- 2011/08/15
CRDT- 2011/08/16 06:00
PHST- 2011/01/06 00:00 [received]
PHST- 2011/06/29 00:00 [accepted]
PHST- 2011/08/16 06:00 [entrez]
PHST- 2011/08/16 06:00 [pubmed]
PHST- 2011/11/01 06:00 [medline]
PHST- 2011/08/15 00:00 [pmc-release]
AID - 46323 [pii]
AID - 10.1172/JCI46323 [doi]
PST - ppublish
SO  - J Clin Invest. 2011 Sep;121(9):3623-34. doi: 10.1172/JCI46323. Epub 2011 Aug 15.