The JNKs differentially regulate RNA polymerase III transcription by coordinately modulating the expression of all TFIIIB subunits.
RNA polymerase (pol) III-dependent transcription is subject to stringent regulation by tumor suppressors and oncogenic proteins and enhanced RNA pol III transcription is essential for cellular transformation and tumorigenesis. Since the c-Jun N-terminal kinases (JNKs) display both oncogenic and tumor suppressor properties, the roles of these proteins in regulating RNA pol III transcription were examined. In both mouse and human cells, loss or reduction in JNK1 expression represses RNA pol III transcription. In contrast, loss or reduction in JNK2 expression induces transcription. The JNKs coordinately regulate expression of all 3 TFIIIB subunits. While JNK1 positively regulates TBP expression, the RNA pol III-specific factors, Brf1 and Bdp1, JNK2 negatively regulates their expression. Brf1 is coregulated with TBP through the JNK target, Elk-1. Reducing Elk-1 expression decreases Brf1 expression. Decreasing JNK1 expression reduces Elk-1 occupancy at the Brf1 promoter, while decreasing JNK2 expression enhances recruitment of Elk-1 to the Brf1 promoter. In contrast, regulation of Bdp1 occurs through JNK-mediated alterations in TBP expression. Altered TBP expression mimics the effect of reduced JNK1 or JNK2 levels on Bdp1 expression. Decreasing JNK1 expression reduces the occupancy of TBP at the Bdp1 promoter, while decreasing JNK2 expression enhances recruitment of TBP to the Bdp1 promoter. Together, these results provide a molecular mechanism for regulating RNA pol III transcription through the coordinate control of TFIIIB subunit expression and elucidate opposing functions for the JNKs in regulating a large class of genes that dictate the biosynthetic capacity of cells.
Zhong
Shuping
S
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Norris Comprehensive Cancer Center, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Johnson
Deborah L
DL
D005786:Gene Expression Regulation; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D048056:Mitogen-Activated Protein Kinase 9 / Q000502:physiology*; D011401:Promoter Regions, Genetic; D021122:Protein Subunits; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics; D012320:RNA Polymerase III / Q000502:physiology*; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics; D035181:TATA-Box Binding Protein / Q000235:genetics / Q000378:metabolism; D035361:Transcription Factor TFIIIB / Q000235:genetics*; D014158:Transcription, Genetic; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
C441028:BRF1 protein, human; D021122:Protein Subunits; D035381:TATA-Binding Protein Associated Factors; D035181:TATA-Box Binding Protein; D035361:Transcription Factor TFIIIB; D050807:ets-Domain Protein Elk-1; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D012320:RNA Polymerase III; C422224:PTPN18 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor