The downregulation of onzin expression by PKCepsilon-ERK2 signaling and its potential role in AML cell differentiation.
Onzin is a small, novel, and highly conserved protein with unique structure and tissue-restricted expression. The regulation of its expression and biological roles remain greatly elusive. Here, we provide the first demonstration that onzin expression is significantly downregulated during differentiation induction of acute myeloid leukemic (AML) cell lines and primary cells by all-trans retinoic acid (ATRA) and especially by phorbol 12-myristate 13-acetate (PMA). Applying chemical inhibitions, RNA interferences, and transfected expressions of dominant negative mutants or constitutive catalytic forms of the related kinases, we show that protein kinase C-epsilon (PKCepsilon)-extracellular signal-regulated protein kinase 2 (ERK2) signaling axis is required for PMA-induced downregulation of onzin expression. The ectopic expression of onzin partially inhibits PMA-induced monocytic differentiation of AML cells, whereas suppression of onzin by specific short hairpin RNAs enhances PMA-induced differentiation to a degree. Furthermore, onzin partially inhibits the transcriptional activity of hematopoiesis-related important transcription factor PU.1 via their interaction. Taken together, our results show that PMA downregulates onzin expression through PKCepsilon-ERK2 signaling pathway, which favors monocytic differentiation of leukemic cells.
Wu
S-F
SF
Institute of Health Science, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences-Shanghai Jiaotong University School of Medicine (SJTU-SM), Shanghai, China.
Huang
Y
Y
Hou
J-K
JK
Yuan
T-T
TT
Zhou
C-X
CX
Zhang
J
J
Chen
G-Q
GQ
D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051744:Protein Kinase C-epsilon / Q000502:physiology*; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D014212:Tretinoin / Q000494:pharmacology; D000099232:Proto-Oncogene Protein Spi-1
D019950:Mitogen-Activated Protein Kinase 1; D015513:Oncogene Proteins; D051744:Protein Kinase C-epsilon; D011506:Proteins; D011518:Proto-Oncogene Proteins; D013755:Tetradecanoylphorbol Acetate; D015534:Trans-Activators; D014212:Tretinoin; D000099232:Proto-Oncogene Protein Spi-1; C506004:PLAC8 protein, human