Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-A gene expression.
Loss of the maintenance of genetic material is a critical step leading to tumorigenesis. It was reported that overexpression of Aurora-A and the constitutive activation of the epidermal growth factor (EGF) receptor (EGFR) are implicated in chromosome instability. In this study, we examined that when cells treated with EGF result in centrosome amplification and microtubule disorder, which are critical for genetic instability. Interestingly, the expression of Aurora-A was also increased by EGF stimulus. An immunofluorescence assay indicated that EGF can induce the nuclear translocation of EGFR. Chromatin immunoprecipitation (ChIP) and re-ChIP assays showed significant EGF-induced recruitment of nuclear EGFR and signal transducer and activator of transcription 5 (STAT5) to the Aurora-A promoter. A co-immunoprecipitation assay further demonstrated that EGF induces nuclear interaction between EGFR and STAT5. A small interfering (si)RNA knockdown assay also showed that EGFR and STAT5 are indeed involved in EGF-increased Aurora-A gene expression. Altogether, this study proposes that the nuclear EGFR associates with STAT5 to bind and increase Aurora-A gene expression, which ultimately may lead to chromosome instability and tumorigenesis. The results also provide a novel linkage between the EGFR signaling pathway and overexpression of Aurora-A in tumorigenesis and chromosome instability.
Hung
Liang-Yi
LY
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. lyhung@mail.ncku.edu.tw
Tseng
Joseph T
JT
Lee
Yi-Chao
YC
Xia
Weiya
W
Wang
Ying-Nai
YN
Wu
Min-Li
ML
Chuang
Yu-Hsuan
YH
Lai
Chein-Hsien
CH
Chang
Wen-Chang
WC
D021581:Active Transport, Cell Nucleus; D000818:Animals; D064127:Aurora Kinases; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D018385:Centrosome / Q000187:drug effects / Q000648:ultrastructure; D043171:Chromosomal Instability / Q000187:drug effects; D006224:Cricetinae; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation
D018160:Receptors, Cytoplasmic and Nuclear; D050799:STAT5 Transcription Factor; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases