Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription.
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.
Gurumurthy
Meera
M
Expression Engineering Group, Bioprocessing Technology Institute, 20 Biopolis Way, #06-01 Centros, Singapore 138668, Singapore.
Tan
Chuan Hao
CH
Ng
Raymond
R
Zeiger
Lisa
L
Lau
Joanne
J
Lee
Jialing
J
Dey
Anwesha
A
Philp
Robin
R
Li
Qintong
Q
Lim
Tit Meng
TM
Price
David H
DH
Lane
David P
DP
Chao
Sheng-Hao
SH
D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D009369:Neoplasms / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012319:RNA Polymerase II / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic
C476123:HEXIM1 protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D000090243:Nucleophosmin; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II