TRB2, a mouse Tribbles ortholog, suppresses adipocyte differentiation by inhibiting AKT and C/EBPbeta.
Adipocyte differentiation is regulated by a complex array of extracellular signals, intracellular mediators and transcription factors. Here we describe suppression of adipocyte differentiation by TRBs, mammalian orthologs of Drosophila Tribbles. Whereas all the three TRBs were expressed in 3T3-L1 preadipocytes, TRB2 and TRB3, but not TRB1, were immediately down-regulated by differentiation stimuli. Forced expression of TRB2 and TRB3 inhibited adipocyte differentiation at an early stage. Akt activation is a key event in adipogenesis and was severely inhibited by TRB3 in 3T3-L1 cells. However, the inhibition by TRB2 was mild compared with severe inhibition by TRB3, though TRB2 suppressed adipogenesis as strongly as TRB3. Interestingly, TRB2 but not TRB3 reduced the level of C/EBPbeta, a transcription factor required for an early stage of adipogenesis, through a proteasome-dependent mechanism. Furthermore, knockdown of endogenous TRB2 by siRNA allowed 3T3-L1 cells to differentiate without full differentiation stimuli. These results suggest that inhibition of Akt activation in combination with degradation of C/EBPbeta is the basis for the strong inhibitory effect of TRB2 on adipogenesis.
Naiki
Takahiro
T
Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Tokyo 113-0032, Japan.
Saijou
Eiko
E
Miyaoka
Yuichiro
Y
Sekine
Keisuke
K
Miyajima
Atsushi
A
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors*; D018797:Cell Cycle Proteins / Q000502:physiology; D002454:Cell Differentiation; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000502:physiology* / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering / Q000494:pharmacology
D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C474830:TRB3 protein, mouse; C523519:Trb1 protein, mouse; C515847:tribbles 2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt