p15RS attenuates Wnt/{beta}-catenin signaling by disrupting {beta}-catenin·TCF4 Interaction.
The formation of a β-catenin·TCF4 complex in the nucleus of cells is well known as a prerequisite for the transcription of Wnt target genes. Although many co-factors have been identified to regulate the activity of the β-catenin·TCF4 complex, it remains unclear how the complex association is negatively regulated. In this study, we report that p15RS, a negative regulator of the cell cycle, blocks β-catenin·TCF4 complex formation and inhibits Wnt signaling. We observed that p15RS interacts with β-catenin and TCF4. Interestingly, whereas the interaction of p15RS with β-catenin is increased, its interaction with TCF4 is decreased upon Wnt1 stimulation. Moreover, overexpression of p15RS reduces the interaction of β-catenin with TCF4, whereas the depletion of p15RS enhances their interaction. We further demonstrate that overexpression of p15RS suppresses canonical Wnt signaling and results in retarded cell growth, whereas depletion of p15RS shows an enhanced effect on Wnt signaling. We analyzed that inhibition of Wnt signaling by p15RS leads to decreased expression of CYCLIN D1 and c-MYC, two Wnt targeted genes critical for cell growth. Our data suggest that p15RS inhibits Wnt signaling by interrupting β-catenin·TCF4 complex formation and that Wnt signaling initiates downstream gene expression by removing p15RS from promoters.
Wu
Yinyuan
Y
School of Medicine, School of Life Sciences, State Key Laboratory of Biomembrane and Membrane Biotechnology, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
Zhang
Yanquan
Y
Zhang
Haiwei
H
Yang
Xi
X
Wang
Yinyin
Y
Ren
Fangli
F
Liu
Huitu
H
Zhai
Yonggong
Y
Jia
Baoqing
B
Yu
Jun
J
Chang
Zhijie
Z
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; C489427:MYC protein, human; D046912:Multiprotein Complexes; D016271:Proto-Oncogene Proteins c-myc; C470426:RPRD1A protein, human; D012097:Repressor Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1