NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting acinus/CtBP2 association.
Cyclin A1 is essential for leukemia progression, and its expression is tightly regulated by acinus, a nuclear speckle protein. However, the molecular mechanism of how acinus mediates cyclin A1 expression remains elusive. Here we show that transcription corepressor CtBP2 directly binds acinus, which is regulated by nerve growth factor (NGF), inhibiting its stimulatory effect on cyclin A1, but not cyclin A2, expression in leukemia. NGF, a cognate ligand for the neurotrophic receptor TrkA, promotes the interaction between CtBP2 and acinus through triggering acinus phosphorylation by Akt. Overexpression of CtBP2 diminishes cyclin A1 transcription, whereas depletion of CtBP2 abolishes NGF's suppressive effect on cyclin A1 expression. Strikingly, gambogic amide, a newly identified TrkA agonist, potently represses cyclin A1 expression, thus blocking K562 cell proliferation. Moreover, gambogic amide ameliorates the leukemia progression in K562 cells inoculated nude mice. Hence, NGF downregulates cyclin A1 expression through escalating CtBP2/acinus complex formation, and gambogic amide might be useful for human leukemia treatment.
Chan
C B
CB
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Liu
X
X
Jang
S-W
SW
Hsu
S I-H
SI
Williams
I
I
Kang
S
S
Chen
J
J
Ye
K
K
D000429:Alcohol Oxidoreductases / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D056970:Co-Repressor Proteins; D056750:Cyclin A1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009243:NAD / Q000502:physiology; D020932:Nerve Growth Factor / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D020917:Receptor, trkA / Q000819:agonists; D044004:Xanthones / Q000494:pharmacology
C121310:ACIN1 protein, human; C503745:CCNA1 protein, human; D056970:Co-Repressor Proteins; D056750:Cyclin A1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D044004:Xanthones; D009243:NAD; D020932:Nerve Growth Factor; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human; D020917:Receptor, trkA; C545053:gambogic amide