Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation.
The Runt domain transcription factors (RUNXs) play essential roles in normal development and neoplasias. Genetic analyses of animals and humans have revealed the involvement of RUNX1 in hematopoiesis and leukemia, RUNX2 in osteogenesis and cleidocranial dysplasia, and RUNX3 in the development of T-cells and dorsal root ganglion neurons and in the genesis of gastric cancer. Here we report that RUNX3 is a target of the acetyltransferase activity of p300. The p300-dependent acetylation of three lysine residues protects RUNX3 from ubiquitin ligase Smurf-mediated degradation. The extent of the acetylation is up-regulated by the transforming growth factor-beta signaling pathway and down-regulated by histone deacetylase activities. Our findings demonstrate that the level of RUNX3 protein is controlled by the competitive acetylation and deacetylation of the three lysine residues, revealing a new mechanism for the posttranslational regulation of RUNX3 expression.
Jin
Yun-Hye
YH
Department of Biochemistry and Urology, School of Medicine and Institute for Tumor Research, Chungbuk National University, Cheongju 361-763, South Korea.
Jeon
Eun-Joo
EJ
Li
Qing-Lin
QL
Lee
Yong Hee
YH
Choi
Joong-Kook
JK
Kim
Wun-Jae
WJ
Lee
Kwang-Youl
KY
Bae
Suk-Chul
SC
D000107:Acetylation; D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D018797:Cell Cycle Proteins; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006877:Hydroxamic Acids; D008239:Lysine; D011500:Protein Synthesis Inhibitors; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C493729:Runx3 protein, human; C012589:trichostatin A; C471641:SMURF2 protein, human