Interplay of Fli-I and FLAP1 for regulation of beta-catenin dependent transcription.
Beta-catenin mediates Wnt/wingless signaling and transcriptional activation by lymphocyte enhancer binding factor 1/T cell factor (LEF1/TCF) proteins with the assistance of multiple coregulators, including positive cofactors like p300/CBP and negative cofactors like HDACs. We previously demonstrated that a developmentally essential protein, Flightless-I (Fli-I), serves as a coactivator for nuclear receptor-mediated transcription. To further understand the action mechanism of Fli-I, we investigated the functional roles of Fli-I and Fli-I leucine rich repeat associated protein 1 (FLAP1) in transcriptional activation by beta-catenin and LEF1/TCF. beta-catenin-dependent transcription was activated by exogenous FLAP1 but inhibited by Fli-I. Reduction of endogenous FLAP1 levels compromised transcriptional activation by LEF1/TCF, beta-catenin and the p160 coactivator GRIP1. FLAP1 interacted directly with beta-catenin, GRIP1 and p300 and enhanced their activity. Furthermore, FLAP1 was strongly synergistic with p300 in supporting transcriptional activation by beta-catenin and LEF1/TCF, but Fli-I disrupted the synergy of FLAP1 with p300 and beta-catenin. Thus the opposing effects of Fli-I and FLAP1 may be a key regulatory mechanism for beta-catenin and LEF1/TCF-mediated transcription and thus for Wnt signaling, and some mutations of Fli-I may result in developmental defects, such as the flightless phenotype of Drosophila, by causing dysregulation of the Wnt/beta-catenin pathway.
Lee
Young-Ho
YH
Department of Biochemistry and Molecular Biology, University of Southern California, 1333 San Pablo Avenue, MCA 51A, Los Angeles, CA 90089, USA.
Stallcup
Michael R
MR
D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008840:Microfilament Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011944:Receptors, Androgen / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D051176:beta Catenin / Q000378:metabolism*; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D051548:Histone Acetyltransferases; D051821:Lymphoid Enhancer-Binding Factor 1; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C098179:FLII protein, human; C491310:GRIP1 protein, human; C114370:LRRFIP1 protein, human