title: TAZ antagonizes the WWP1-mediated KLF5 degradation and promotes breast cell proliferation and tumorigenesis.
abstract: Krüppel-like factor 5 (KLF5) is a PY motif-containing transcription factor promoting breast cell proliferation. The KLF5 protein is rapidly degraded through the proteasome after ubiquitination by E3 ubiquitin ligases, such as WWP1 and SCF(Fbw7). In this study, we demonstrated that a transcriptional co-activator with the PDZ-binding motif (TAZ) upregulated the KLF5 expression through antagonizing the WWP1-, but not Fbw7-, mediated KLF5 ubiquitination and degradation. TAZ interacted with KLF5 through the WW domain of TAZ and the PY motif of KLF5, which is the binding site for WWP1. TAZ inhibited WWP1-KLF5 protein interaction and WWP1-mediated KLF5 ubiquitination and degradation in a WW domain-dependent manner. Overexpression of TAZ upregulated the protein levels of KLF5 and FGF-BP, which is a well-established KLF5 target gene. In addition, depletion of TAZ in both 184A1 and HCC1937 breast cells downregulated protein levels of KLF5 and FGF-BP and inhibited cell growth. Furthermore, stable depletion of either TAZ or KLF5 significantly suppressed HCC1937 xenograft growth in immunodeficient mice. Knockdown of LATS1, a TAZ upstream inhibitory kinase, up-regulated the protein levels of KLF5 and FGF-BP in 184A1 and promoted cell growth through TAZ. Finally, both KLF5 and TAZ were co-expressed in a subset of estrogen receptor α-negative breast cell lines. These results, for the first time, suggest that TAZ promotes breast cell growth partially through protecting KLF5 from WWP1-mediated degradation and enhancing KLF5's activities.
authors: Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China.
authors: Dong
authors: D
authors: Zhao
authors: Xu
authors: X
authors: Zhi
authors: Zhongmei
authors: Z
authors: Zhou
authors: Ceshi
authors: C
authors: Chen
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D025521:Tumor Suppressor Proteins / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; D025521:Tumor Suppressor Proteins; C551991:WWTR1 protein, human; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex