Cancer-associated splicing variant of tumor suppressor AIMP2/p38: pathological implication in tumorigenesis

Autor: Bora Kim, Soon Kyung Hwang, Jhingook Kim, Sunghoon Kim, Nam Hoon Kwon, Myung-Haing Cho, Hyerim Kim, Seung Hyun Oh, Hyo Sung Jeon, Jin Woo Choi, Jin Young Lee, Seung Hee Chang, Jae Yong Park, Yoon La Choi, Al Eum Lee, Young Kee Shin, Hyunseok Peter Kang, Soo Youl Kim, Jung Min Han, Bum Joon Park, Dae Gyu Kim
Jazyk: angličtina
Rok vydání: 2011
Předmět:
Male
Cancer Research
Programmed cell death
Lung Neoplasms
lcsh:QH426-470
Adenocarcinoma of Lung
Apoptosis
Biology
Molecular Biology/RNA Splicing
Adenocarcinoma
medicine.disease_cause
law.invention
Amino Acyl-tRNA Synthetases
Exon
Mice
law
Cell Line
Tumor
Genetics
medicine
Animals
Humans
Lung cancer
Molecular Biology
Genetics (clinical)
Ecology
Evolution
Behavior and Systematics
Cell Biology/Gene Expression
Oncology/Lung Cancer
Aged
Neoplasm Staging
Alternative splicing
Cancer
Cell Biology
Cell Biology/Cellular Death and Stress Responses
Exons
Middle Aged
medicine.disease
Molecular biology
Survival Analysis
Gene Expression Regulation
Neoplastic
Alternative Splicing
lcsh:Genetics
Cell Transformation
Neoplastic
RNA splicing
Cancer research
Suppressor
Female
Tumor Suppressor Protein p53
Carcinogenesis
Research Article
Zdroj: PLoS Genetics, Vol 7, Iss 3, p e1001351 (2011)
PLoS Genetics
ISSN: 1553-7404
1553-7390
Popis: Although ARS-interacting multifunctional protein 2 (AIMP2, also named as MSC p38) was first found as a component for a macromolecular tRNA synthetase complex, it was recently discovered to dissociate from the complex and work as a potent tumor suppressor. Upon DNA damage, AIMP2 promotes apoptosis through the protective interaction with p53. However, it was not demonstrated whether AIMP2 was indeed pathologically linked to human cancer. In this work, we found that a splicing variant of AIMP2 lacking exon 2 (AIMP2-DX2) is highly expressed by alternative splicing in human lung cancer cells and patient's tissues. AIMP2-DX2 compromised pro-apoptotic activity of normal AIMP2 through the competitive binding to p53. The cells with higher level of AIMP2-DX2 showed higher propensity to form anchorage-independent colonies and increased resistance to cell death. Mice constitutively expressing this variant showed increased susceptibility to carcinogen-induced lung tumorigenesis. The expression ratio of AIMP2-DX2 to normal AIMP2 was increased according to lung cancer stage and showed a positive correlation with the survival of patients. Thus, this work identified an oncogenic splicing variant of a tumor suppressor, AIMP2/p38, and suggests its potential for anti-cancer target.
Author Summary Lung cancer is one of the most common cancers and a leading cause of death resulting from cancer. Despite intensive investigation, effective therapeutic targets and reliable biomarkers are still limited. Here we found that a tumor suppressor, AIMP2 (MSC p38), produces a variant lacking a part of its structure in cancer tissues. We designated it AIMP2-DX2. This smaller version of AIMP2 compromises the normal tumor suppressive activity of AIMP2 and induces tumor formation. We also found that the expression of AIMP2-DX2 was increased according to cancer progression. In addition, the patients with higher expression of AIMP2-DX2 showed lower survival than those with lower levels of this variant. Suppression of AIMP2-DX2 slowed tumor growth, suggesting it as a new therapeutic target. In summary, this work newly identified a tumor-inducing factor, AIMP2-DX2, that can be used as a therapeutic target and biomarker associated with lung cancer.
Databáze: OpenAIRE
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