Leukemia-related transcription factor TEL is negatively regulated through extracellular signal-regulated kinase-induced phosphorylation.
TEL is an ETS family transcription factor that possesses multiple putative mitogen-activated protein kinase phosphorylation sites. We here describe the functional regulation of TEL via ERK pathways. Overexpressed TEL becomes phosphorylated in vivo by activated ERK. TEL is also directly phosphorylated in vitro by ERK. The inducible phosphorylation sites are Ser(213) and Ser(257). TEL binds to a common docking domain in ERK. In vivo ERK-dependent phosphorylation reduces trans-repressional and DNA-binding abilities of TEL for ETS-binding sites. A mutant carrying substituted glutamates on both Ser(213) and Ser(257) functionally mimics hyperphosphorylated TEL and also shows a dominant-negative effect on TEL-induced transcriptional suppression. Losing DNA-binding affinity through phosphorylation but heterodimerizing with unmodified TEL could be an underlying mechanism. Moreover, the glutamate mutant dominantly interferes with TEL-induced erythroid differentiation in MEL cells and growth suppression in NIH 3T3 cells. Finally, endogenous TEL is dephosphorylated in parallel with ERK inactivation in differentiating MEL cells and is phosphorylated through ERK activation in Ras-transformed NIH 3T3 cells. These data indicate that TEL is a constituent downstream of ERK in signal transduction systems and is physiologically regulated by ERK in molecular and biological features.
Maki
Kazuhiro
K
Department of Hematology, Dokkyo University School of Medicine, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan.
Arai
Honoka
H
Waga
Kazuo
K
Sasaki
Ko
K
Nakamura
Fumihiko
F
Imai
Yoichi
Y
Kurokawa
Mineo
M
Hirai
Hisamaru
H
Mitani
Kinuko
K
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D000097764:ETS Translocation Variant 6 Protein
D004268:DNA-Binding Proteins; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D012694:Serine; D000097764:ETS Translocation Variant 6 Protein