RAF-1/MEK/ERK pathway regulates ATRA-induced differentiation in acute promyelocytic leukemia cells through C/EBPβ, C/EBPε and PU.1.
MEK/ERK signal pathway was required for the differentiation of granulocytes, megakaryocytes and erythrocytes. Recently, MEK/ERK cascade was reported to be involved in all-trans retinoic acid (ATRA) induced differentiation in acute promyelocytic leukemia (APL) cells. However, the upstream and downstream molecules of MEK/ERK signal pathway in this cell model remains to be elucidated. In this work, we showed that RAF-1 was activated and the blockade of RAF-1 activation attenuated MEK/ERK activation as well as ATRA-induced differentiation. ATRA-enhanced protein levels of C/EBPβ, C/EBPε and PU.1, which were required for differentiation in APL cells, were suppressed by the specific inhibitor of MEK. However, MEK inhibition had no effect on the degradation of PML-RARα fusion protein or the restoration of PML nuclear bodies by ATRA treatment. Taken together, our study suggested that RAF-1/MEK/ERK cascade was involved in ATRA-induced differentiation in APL cells through enhancing the protein level of C/EBPβ, C/EBPε and PU.1.
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Xiang-Qin
XQ
Weng
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Yan
Y
Sheng
Department of Hematology, Peace Hospital of Changzhi Medical College, Changzhi 046000, China.
Dong-Zheng
DZ
Ge
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Jing
J
Wu
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Lei
L
Shi
Shanghai Institute of Hematology and State Key Laboratory of Medical Genomics, Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: xuncai@yahoo.com.
Xun
X
Cai
D000970:Antineoplastic Agents / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D000099232:Proto-Oncogene Protein Spi-1
D000970:Antineoplastic Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; D011518:Proto-Oncogene Proteins; D019908:Proto-Oncogene Proteins c-raf; D015534:Trans-Activators; D014212:Tretinoin; D000099232:Proto-Oncogene Protein Spi-1; C070790:CEBPE protein, human
Acute promyelocytic leukemia; All-trans retinoic acid; Differentiation; MEK