Interaction of TIF-90 and filamin A in the regulation of rRNA synthesis in leukemic cells.
The transcription initiation factor I (TIF-IA) is an important regulator of the synthesis of ribosomal RNA (rRNA) through its facilitation of the recruitment of RNA polymerase I (Pol I) to the ribosomal DNA promoter. Activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway, which occurs commonly in acute myelogenous leukemia, enhances rRNA synthesis through TIF-IA stabilization and phosphorylation. We have discovered that TIF-IA coexists with a splicing isoform, TIF-90, which is expressed preferentially in the nucleolus and at higher levels in proliferating and transformed hematopoietic cells. TIF-90 interacts directly with Pol I to increase rRNA synthesis as a consequence of Akt activation. Furthermore, TIF-90 binds preferentially to a 90-kDa cleavage product of the actin binding protein filamin A (FLNA) that inhibits rRNA synthesis. Increased expression of TIF-90 overcomes the inhibitory effect of this cleavage product and stimulates rRNA synthesis. Because activated Akt also reduces FLNA cleavage, these results indicate that activated Akt and TIF-90 function in parallel to increase rRNA synthesis and, as a consequence, cell proliferation in leukemic cells. These results provide evidence that the direct targeting of Akt would be an effective therapy in acute leukemias in which Akt is activated.
Department of Medicine, Stanford Cancer Institute, and.
Le Xuan Truong
le XT
Nguyen
Department of Medicine, Stanford Cancer Institute, and Department of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA; and.
Steven M
SM
Chan
Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea.
Tri Duc
TD
Ngo
Department of Medicine, Stanford Cancer Institute, and.
Aparna
A
Raval
Department of Molecular Cell Biology, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea.
Kyeong Kyu
KK
Kim
Department of Medicine, Stanford Cancer Institute, and Department of Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA; and.
Ravindra
R
Majeti
Department of Medicine, Stanford Cancer Institute, and.
Beverly S
BS
Mitchell
D017398:Alternative Splicing; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000235:genetics; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D064448:Filamins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012335:RNA, Ribosomal / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012270:Ribosomes / Q000378:metabolism*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D009218:Myosins
D051017:Apoptosis Regulatory Proteins; D064448:Filamins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D012335:RNA, Ribosomal; C578663:FLNA protein, human; C407152:MYO18A protein, human; D009218:Myosins