PMID- 17575144
OWN - NLM
STAT- MEDLINE
DCOM- 20070925
LR  - 20201209
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 67
IP  - 12
DP  - 2007 Jun 15
TI  - Expression of DNA methyltransferase 1 is activated by hepatitis B virus X protein 
      via a regulatory circuit involving the p16INK4a-cyclin D1-CDK 4/6-pRb-E2F1 
      pathway.
PG  - 5771-8
AB  - DNA methyltransferase 1 (DNMT1) is responsible for copying DNA methylation 
      patterns to the daughter strands during DNA replication. Its expression is 
      frequently up-regulated in human tumors, including hepatocellular carcinoma, but 
      the mechanism of overexpression and its biological significance remain unclear. 
      Here, we show that hepatitis B virus X protein (HBx) activates DNMT1 expression 
      via a regulatory circuit involving the p16(INK4a)-cyclin D1-cyclin-dependent 
      kinase (CDK) 4/6-retinoblastoma protein (pRb)-E2F1 pathway. HBx induced DNA 
      hypermethylation of p16(INK4a) promoter to repress its expression, which 
      subsequently led to activation of G1-CDKs, phosphorylation of pRb, activation of 
      E2F1, and finally transcriptional activation of DNMT1. Inhibition of DNMT1 
      activity by either treatment with 5'-Aza-2'dC or introduction of DNMT1 small 
      interfering RNA not only abolished the DNA methylation-mediated p16(INK4a) 
      repression but also impaired DNMT1 expression itself, suggesting a cross-talk 
      between DNMT1 and p16(INK4a). The up-regulation of cyclin D1 by HBx is likely to 
      serve as an initiative impulse for the circuit because it was absolutely required 
      for the activation of DNMT1 expression. We also observed that accumulated DNMT1 
      via this pathway inactivates E-cadherin expression through promoter 
      hypermethylation. Considering that the pRb-E2F1 pathway is commonly activated in 
      human tumors, activation of this circuit might be widespread and a potential 
      therapeutic target.
FAU - Jung, Jin Kyu
AU  - Jung JK
AD  - Division of Biological Sciences, College of Natural Sciences, Pusan National 
      University, Busan, Korea.
FAU - Arora, Payal
AU  - Arora P
FAU - Pagano, Joseph S
AU  - Pagano JS
FAU - Jang, Kyung Lib
AU  - Jang KL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Cadherins)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p16)
RN  - 0 (E2F1 Transcription Factor)
RN  - 0 (E2F1 protein, human)
RN  - 0 (Retinoblastoma Protein)
RN  - 0 (Trans-Activators)
RN  - 0 (Viral Regulatory and Accessory Proteins)
RN  - 0 (hepatitis B virus X protein)
RN  - 136601-57-5 (Cyclin D1)
RN  - EC 2.1.1.- (DNA Modification Methylases)
RN  - EC 2.7.11.22 (CDK4 protein, human)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
SB  - IM
MH  - Blotting, Western
MH  - Cadherins/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cyclin D1/metabolism
MH  - Cyclin-Dependent Kinase 4/metabolism
MH  - Cyclin-Dependent Kinase Inhibitor p16/metabolism
MH  - DNA Methylation
MH  - DNA Modification Methylases/*biosynthesis
MH  - E2F1 Transcription Factor/*metabolism
MH  - Humans
MH  - RNA Interference
MH  - Retinoblastoma Protein/*metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*physiology
MH  - Trans-Activators/*metabolism
MH  - Transfection
MH  - Viral Regulatory and Accessory Proteins
EDAT- 2007/06/19 09:00
MHDA- 2007/09/26 09:00
CRDT- 2007/06/19 09:00
PHST- 2007/06/19 09:00 [pubmed]
PHST- 2007/09/26 09:00 [medline]
PHST- 2007/06/19 09:00 [entrez]
AID - 67/12/5771 [pii]
AID - 10.1158/0008-5472.CAN-07-0529 [doi]
PST - ppublish
SO  - Cancer Res. 2007 Jun 15;67(12):5771-8. doi: 10.1158/0008-5472.CAN-07-0529.