Journal article
Nucleophosmin Interacts with HEXIM1 and Regulates RNA Polymerase II Transcription
Journal of molecular biology, Vol.378(2), pp.302-317
04/25/2008
DOI: 10.1016/j.jmb.2008.02.055
PMID: 18371977
Abstract
Hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) was identified earlier as an inhibitor of positive transcription elongation factor b (P-TEFb), which is a key transcriptional regulator of RNA polymerase II (Pol II). Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. Here, we identify a nucleolar protein, nucleophosmin (NPM), as a HEXIM1-binding protein. NPM binds to HEXIM1 in vitro and in vivo, and functions as a negative regulator of HEXIM1. Over-expression of NPM leads to proteasome-mediated degradation of HEXIM1, resulting in activation of P-TEFb-dependent transcription. In contrast, an increase in HEXIM1 protein levels and a decrease in transcription are detected when NPM is knocked down. We show that a cytoplasmic mutant of NPM, NPMc+, associates with and sequesters HEXIM1 in the cytoplasm resulting in higher RNA Pol II transcription. Correspondingly, cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction. Over-expression of NPM has been detected in tumors of various histological origins and our results may provide a possible molecular mechanism for the proto-oncogenic function of NPM. Furthermore, considering that 35% of AML patients are diagnosed with NPMc+ mutation, our findings suggest that in some cases of AML, RNA Pol II transcription may be disregulated by the malfunction of NPM and the mislocation of HEXIM1.
Details
- Title: Subtitle
- Nucleophosmin Interacts with HEXIM1 and Regulates RNA Polymerase II Transcription
- Creators
- Meera Gurumurthy - Expression Engineering Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, SingaporeChuan Hao Tan - Expression Engineering Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, SingaporeRaymond Ng - Expression Engineering Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, SingaporeLisa Zeiger - Expression Engineering Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, SingaporeJoanne Lau - Expression Engineering Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, SingaporeJialing Lee - Expression Engineering Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, SingaporeAnwesha Dey - Department of Cell Cycle Control, Institute of Molecular and Cell Biology, Proteos, Singapore 138668, SingaporeRobin Philp - Proteomics Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, SingaporeQintong Li - Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USATit Meng Lim - Department of Biological Sciences, National University of Singapore, Science Drive 4, Blk S1A #05-36, Singapore 117543, SingaporeDavid H Price - Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USADavid P Lane - Department of Cell Cycle Control, Institute of Molecular and Cell Biology, Proteos, Singapore 138668, SingaporeSheng-Hao Chao - Expression Engineering Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore
- Resource Type
- Journal article
- Publication Details
- Journal of molecular biology, Vol.378(2), pp.302-317
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/j.jmb.2008.02.055
- PMID
- 18371977
- ISSN
- 0022-2836
- eISSN
- 1089-8638
- Language
- English
- Date published
- 04/25/2008
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984024519402771
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