PMID- 22133874
OWN - NLM
STAT- MEDLINE
DCOM- 20120306
LR  - 20231213
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 122
IP  - 1
DP  - 2012 Jan
TI  - Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse 
      lymphomagenesis.
PG  - 163-77
LID - 57292 [pii]
LID - 10.1172/JCI57292 [doi]
AB  - DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for 
      methylation of cytosine residues in mammals. DNA methylation contributes to the 
      epigenetic control of gene transcription and is deregulated in virtually all 
      human tumors. To better understand the generation of cancer-specific methylation 
      patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced 
      lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T 
      cells accelerated lymphomagenesis by increasing cellular proliferation, which 
      suggests that Dnmt3b functions as a tumor suppressor. Global methylation 
      profiling revealed numerous gene promoters as potential targets of Dnmt3b 
      activity, the majority of which were demethylated in Dnmt3b-/- lymphomas, but not 
      in Dnmt3b-/- pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine 
      methylation in cancer. Functional analysis identified the gene Gm128 (which we 
      termed herein methylated in normal thymocytes [Ment]) as a target of Dnmt3b 
      activity. We found that Ment was gradually demethylated and overexpressed during 
      tumor progression in Dnmt3b-/- lymphomas. Similarly, MENT was overexpressed in 
      67% of human lymphomas, and its transcription inversely correlated with 
      methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth 
      of mouse and human cells, whereas overexpression of Ment provided Dnmt3b+/+ cells 
      with a proliferative advantage. Our findings identify Ment as an enhancer of 
      lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and 
      suggest it could be a potential target for anticancer therapies.
FAU - Hlady, Ryan A
AU  - Hlady RA
AD  - Eppley Institute for Research in Cancer and Allied Diseases, University of 
      Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
FAU - Novakova, Slavomira
AU  - Novakova S
FAU - Opavska, Jana
AU  - Opavska J
FAU - Klinkebiel, David
AU  - Klinkebiel D
FAU - Peters, Staci L
AU  - Peters SL
FAU - Bies, Juraj
AU  - Bies J
FAU - Hannah, Jay
AU  - Hannah J
FAU - Iqbal, Javeed
AU  - Iqbal J
FAU - Anderson, Kristi M
AU  - Anderson KM
FAU - Siebler, Hollie M
AU  - Siebler HM
FAU - Smith, Lynette M
AU  - Smith LM
FAU - Greiner, Timothy C
AU  - Greiner TC
FAU - Bastola, Dhundy
AU  - Bastola D
FAU - Joshi, Shantaram
AU  - Joshi S
FAU - Lockridge, Oksana
AU  - Lockridge O
FAU - Simpson, Melanie A
AU  - Simpson MA
FAU - Felsher, Dean W
AU  - Felsher DW
FAU - Wagner, Kay-Uwe
AU  - Wagner KU
FAU - Chan, Wing C
AU  - Chan WC
FAU - Christman, Judith K
AU  - Christman JK
FAU - Opavsky, Rene
AU  - Opavsky R
LA  - eng
GR  - P20 RR16469/RR/NCRR NIH HHS/United States
GR  - 2P20RR018788-06/RR/NCRR NIH HHS/United States
GR  - P20 RR016469/RR/NCRR NIH HHS/United States
GR  - P20 RR018788/RR/NCRR NIH HHS/United States
GR  - P20 RR018759/RR/NCRR NIH HHS/United States
GR  - 1S10RR027754-01/RR/NCRR NIH HHS/United States
GR  - S10 RR027754/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111201
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (DNA, Neoplasm)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases)
SB  - IM
MH  - Animals
MH  - Cell Proliferation
MH  - DNA (Cytosine-5-)-Methyltransferases/*deficiency/genetics
MH  - DNA Methylation/genetics
MH  - DNA, Neoplasm/genetics/metabolism
MH  - Disease Models, Animal
MH  - Gene Expression Regulation, Neoplastic
MH  - Genomic Instability
MH  - Humans
MH  - Lymphoma/*etiology/genetics/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - *Oncogenes
MH  - T-Lymphocytes/immunology/pathology
MH  - Tumor Suppressor Proteins/deficiency/genetics
MH  - Up-Regulation
MH  - DNA Methyltransferase 3B
PMC - PMC3248285
EDAT- 2011/12/03 06:00
MHDA- 2012/03/07 06:00
PMCR- 2011/12/01
CRDT- 2011/12/03 06:00
PHST- 2011/01/27 00:00 [received]
PHST- 2011/10/12 00:00 [accepted]
PHST- 2011/12/03 06:00 [entrez]
PHST- 2011/12/03 06:00 [pubmed]
PHST- 2012/03/07 06:00 [medline]
PHST- 2011/12/01 00:00 [pmc-release]
AID - 57292 [pii]
AID - 10.1172/JCI57292 [doi]
PST - ppublish
SO  - J Clin Invest. 2012 Jan;122(1):163-77. doi: 10.1172/JCI57292. Epub 2011 Dec 1.