PMID- 24335704
OWN - NLM
STAT- MEDLINE
DCOM- 20140312
LR  - 20211021
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 111
IP  - 1
DP  - 2014 Jan 7
TI  - Human herpesvirus 6 (HHV-6) alters E2F1/Rb pathways and utilizes the E2F1 
      transcription factor to express viral genes.
PG  - 451-6
LID - 10.1073/pnas.1308854110 [doi]
AB  - E2F transcription factors play pivotal roles in controlling the expression of 
      genes involved in cell-cycle progression. Different viruses affect 
      E2F1/retinoblastoma (Rb) interactions by diverse mechanisms releasing E2F1 from 
      its suppressor Rb, enabling viral replication. We show that in T cells infected 
      with human herpesvirus 6A (HHV-6A), the E2F1 protein and its cofactor DP1 
      increased, whereas the Rb protein underwent massive degradation without 
      hyperphosphorylation at three sites known to control E2F/Rb association. Although 
      E2F1 and DP1 increased without Rb suppression, the E2F1 target genes-including 
      cyclin A, cyclin E, and dihydrofolate reductase-were not up-regulated. To test 
      whether the E2F1/DP1 complexes were used for viral transcription, we scanned the 
      viral genome for genes containing the E2F binding site in their promoters. In the 
      present work, we concentrated on the U27 and U79 genes known to act in viral DNA 
      synthesis. We constructed amplicon-6 vectors containing a GFP reporter gene 
      driven by WT viral promoter or by promoter mutated in the E2F binding site. We 
      found that the expression of the fusion U27 promoter was dependent on the 
      presence of the E2F binding site. Test of the WT U79 promoter yielded >10-fold 
      higher expression of the GFP reporter gene than the mutant U79 promoter with 
      abrogated E2F binding site. Moreover, by using siRNA to E2F1, we found that E2F1 
      was essential for the activity of the U79 promoter. These findings revealed a 
      unique pathway in HHV-6 replication: The virus causes Rb degradation and uses the 
      increased E2F1 and DP1 factors to transcribe viral genes.
FAU - Sharon, Eyal
AU  - Sharon E
AD  - Department of Cell Research and Immunology and the S. Daniel Abraham Institute 
      for Molecular Virology, Tel Aviv University, Tel Aviv 69978, Israel.
FAU - Volchek, Ludmila
AU  - Volchek L
FAU - Frenkel, Niza
AU  - Frenkel N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131212
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Cyclin A)
RN  - 0 (Cyclin E)
RN  - 0 (DNA Primers)
RN  - 0 (E2F1 Transcription Factor)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Retinoblastoma Protein)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
SB  - IM
MH  - Binding Sites
MH  - CD4-Positive T-Lymphocytes/cytology
MH  - Cyclin A/metabolism
MH  - Cyclin E/metabolism
MH  - DNA Primers/genetics
MH  - E2F1 Transcription Factor/*metabolism
MH  - *Gene Expression Regulation, Viral
MH  - Genes, Reporter
MH  - Genes, Viral
MH  - Genome, Viral
MH  - Green Fluorescent Proteins/metabolism
MH  - HEK293 Cells
MH  - Herpesvirus 6, Human/*metabolism
MH  - Humans
MH  - Plasmids/metabolism
MH  - RNA, Small Interfering/metabolism
MH  - Retinoblastoma Protein/*metabolism
MH  - Tetrahydrofolate Dehydrogenase/metabolism
MH  - Time Factors
PMC - PMC3890880
COIS- The authors declare no conflict of interest.
EDAT- 2013/12/18 06:00
MHDA- 2014/03/13 06:00
PMCR- 2013/12/12
CRDT- 2013/12/17 06:00
PHST- 2013/12/17 06:00 [entrez]
PHST- 2013/12/18 06:00 [pubmed]
PHST- 2014/03/13 06:00 [medline]
PHST- 2013/12/12 00:00 [pmc-release]
AID - 1308854110 [pii]
AID - 201308854 [pii]
AID - 10.1073/pnas.1308854110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):451-6. doi: 10.1073/pnas.1308854110. 
      Epub 2013 Dec 12.