Tumor suppressor HLJ1 binds and functionally alters nucleophosmin via activating enhancer binding protein 2alpha complex formation.

Abstract

HLJ1, a member of the heat shock protein 40 chaperone family, is a newly identified tumor suppressor that has been implicated in tumorigenesis and metastasis in non-small cell lung cancer. However, the mechanism of HLJ1 action is presently obscure. In this study, we report that HLJ1 specifically interacts with the nuclear protein nucleophosmin (NPM1), forming a multiprotein complex that alters the nucleolar distribution and oligomerization state of NPM1. Enforced accumulation of NPM1 oligomers by overexpression in weakly invasive but high HLJ1-expressing cells induced the activity of signal transducer and activator of transcription 3 (STAT3) and increased cellular migration, invasiveness, and colony formation. Furthermore, silencing HLJ1 accelerated NPM1 oligomerization, inhibited the activity of transcription corepressor activating enhancer binding protein 2alpha (AP-2alpha), and increased the activities of matrix metalloproteinase-2 (MMP-2) and STAT3. Our findings suggest that HLJ1 switches the role of NPM1, which can act as tumor suppressor or oncogene, by modulating the oligomerization of NPM1 via HLJ1-NPM1 heterodimer formation and recruiting AP-2alpha to the MMP-2 promoter.

• Authors: Tzu-Pei Chang, Sung-Liang Yu, Sheng-Yi Lin, Yi-Jing Hsiao, Gee-Chen Chang, Pan-Chyr Yang, Jeremy J W Chen
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 4 Pg. 1656-67 (Feb 15 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20145123 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNAJB4 protein, human
• HSP40 Heat-Shock Proteins
• Multiprotein Complexes
• NPM1 protein, human
• Nuclear Proteins
• Transcription Factor AP-2
• Tumor Suppressor Proteins
• Nucleophosmin
• MMP2 protein, human
• Matrix Metalloproteinase 2

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• Cell Nucleus (metabolism)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• HSP40 Heat-Shock Proteins (genetics, metabolism, physiology)
• Humans
• Lung Neoplasms (genetics, metabolism, pathology)
• Matrix Metalloproteinase 2 (genetics)
• Multiprotein Complexes (metabolism, physiology)
• Neoplasm Invasiveness
• Nuclear Proteins (chemistry, metabolism, physiology)
• Nucleophosmin
• Protein Binding (genetics, physiology)
• Protein Multimerization (genetics)
• Protein Structure, Tertiary (physiology)
• Protein Transport (genetics)
• Transcription Factor AP-2 (metabolism, physiology)
• Transfection
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (metabolism, physiology)