Language:

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis

Proceedings of the National Academy of Sciences - PNAS, 2015-07, Vol.112 (29), p.9088-9093 [Peer Reviewed Journal]

Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles ;Copyright National Academy of Sciences Jul 21, 2015 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1510757112 ;PMID: 26150517

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis
Author: Jin, Shengfang ; Jiang Chen ; Lizao Chen ; Gavin Histen ; Zhizhong Lin ; Stefan Gross ; Jeffrey Hixon ; Yue Chen ; Charles Kung ; Yiwei Chen ; Yufei Fu ; Yuxuan Lu ; Hui Lin ; Xiujun Cai ; Hua Yang ; Rob A. Cairns ; Marion Dorsch ; Shinsan M. Su ; Scott Biller ; Tak W. Mak ; Yong Cang
Subjects: alcohol drinking ; alcohol metabolism ; Alcoholic Intoxication - enzymology ; Alcoholic Intoxication - pathology ; alcohols ; Aldehyde Dehydrogenase - genetics ; Aldehyde Dehydrogenase, Mitochondrial ; Aldehydes ; ALDH22 polymorphism ; Amino Acid Substitution ; Animals ; Asian flush ; Asians ; Base Sequence ; Biological Sciences ; Carcinogenesis - pathology ; Carcinoma, Hepatocellular - enzymology ; Carcinoma, Hepatocellular - genetics ; Carcinoma, Hepatocellular - pathology ; clinical trials ; Ethanol - adverse effects ; Gene Knock-In Techniques ; Genotype & phenotype ; Genotyping Techniques ; Hepatocytes - enzymology ; Hepatocytes - pathology ; Humans ; Hyperpigmentation - pathology ; Immunohistochemistry ; liver ; Liver - enzymology ; Liver - pathology ; liver cancer ; liver neoplasms ; Liver Neoplasms - enzymology ; Liver Neoplasms - genetics ; Liver Neoplasms - pathology ; Metabolism ; mice ; Mice, Inbred C57BL ; mouse model ; Mutant Proteins - metabolism ; Mutation ; Mutation - genetics ; Polymorphism, Genetic ; Proteasome Endopeptidase Complex - metabolism ; protein metabolism ; Protein Stability ; risk factors ; Skin - pathology ; Survival Analysis ; Toxicity ; Tumors
Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2015-07, Vol.112 (29), p.9088-9093
Description: Mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2*2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2*2 alleleâalcohol interaction may be an even greater human public health hazard than previously appreciated. About 40% of East Asians and over 500 million people worldwide carry a specific polymorphism, ALDH2*2, and exhibit âAsian flushâ after alcohol drinking. We generated a mouse strain with this engineered polymorphism and demonstrated its resemblance to human carriers in terms of defective alcohol metabolism. With this model, we show that murine ALDH2*2 increases ALDH2 protein turnover and promotes chemical-induced liver tumor development. Importantly, ALDH2 is unstable in ALDH2*2 human liver samples and is significantly down-regulated in human liver tumors. Data from our mouse and clinical studies suggest that ALDH2 is a liver tumor suppressor and the ALDH2*2 polymorphism is a risk factor for liver cancer.
Publisher: United States: National Academy of Sciences
Language: English
Identifier: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.1510757112
PMID: 26150517
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis

Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles ;Copyright National Academy of Sciences Jul 21, 2015 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1510757112 ;PMID: 26150517

Searching Remote Databases, Please Wait