KLF5 promotes breast cell survival partially through fibroblast growth factor-binding protein 1-pERK-mediated dual specificity MKP-1 protein phosphorylation and stabilization.
Krüpple-like transcription factor 5 (KLF5) is a zinc-finger transcription factor promoting cell survival and tumorigenesis in multiple cancers. A high expression level of KLF5 has been shown to be associated with shorter breast cancer patient survival. However, the role of KLF5 and mechanism of KLF5 actions in breast cancer remain unclear. In this study, we found that KLF5 knockdown by small interfering RNA in two breast cell lines, MCF10A and BT20, induces apoptosis. Interestingly, a pro-survival phosphatase, dual specificity mitogen-activated protein kinase phosphatase 1 (MKP-1), is down-regulated by KLF5 ablation. Consistently, KLF5 overexpression increases the MKP-1 protein expression in Hs578T and MCF7. We further found that MKP-1 is essential and sufficient for KLF5 to promote breast cell survival. However, MKP-1 is not a KLF5 direct transcription target because the MKP-1 mRNA level is not regulated by KLF5. By cycloheximide chase assays, we found that KLF5 decreases MKP-1 protein degradation via activating the ERK signaling. Inhibition of pERK by the pharmacological inhibitor U0126 specifically blocks KLF5-induced MKP-1 phosphorylation and stabilization. Additionally, constitutive activation of ERK by constitutively activated MEK1 rescues the KLF5 depletion-induced MKP-1 down-regulation. Consistently, the phosphorylation-deficient MKP-1 mutant cannot be stabilized by KLF5. Finally, the activation of ERK by KLF5 is very likely through the KLF5 direct target gene FGF-BP in breast cells. These findings suggest that KLF5 is a pro-survival factor that promotes breast cell survival partially through pERK-mediated MKP-1 phosphorylation and stabilization. The KLF5-FGF-BP-pERK-MKP-1 signaling axis may provide new therapeutic targets for invasive breast cancer.
Liu
Rong
R
From the Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208.
Zheng
Han-Qiu
HQ
From the Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208.
Zhou
Zhongmei
Z
From the Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208.
Dong
Jin-Tang
JT
Winship Cancer Institute and Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, Georgia 30322.
Chen
Ceshi
C
From the Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208. Electronic address: chenc@mail.amc.edu.
D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D004795:Enzyme Stability; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
D002352:Carrier Proteins; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins; C492214:KLF5 protein, human; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; C070699:FGFBP1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1