Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-A gene expression

Abstract

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.

Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab

“…32 Nuclear EGFR is known to regulate the promoters of several target genes including, Cyclin D1, 23 iNOS, 29 B-myb, 34 Aurora Kinase A 35 and COX2. 31 Mechanisms of EGFR-mediated gene regulation involve direct interaction of EGFR with STAT3 to regulate iNOS 29 and COX2, 31 promoters, with STAT5 for regulation of the Aurora Kinase A promoter, 35 and with E2F1 transcription factors for regulation of the B-Myb promoter. 34 Nuclear EGFR has also recently been shown to function as a tyrosine kinase in the nucleus, phosphorylating and stabilizing PCNA and thus enhancing the proliferative potential of cancer cells.…”

Structure of Sad1-UNC84 Homology (SUN) Domain Defines Features of Molecular Bridge in Nuclear Envelope

“…Defects of NE proteins have been associated with various severe human diseases and anomalies, such as muscular dystrophy and progeria syndrome (2)(3)(4)(5)(6). The nuclear lamin network may also interact with pools of ErbB receptors directed to nuclear sites (7)(8)(9)(10).…”

RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus

“…Nuclear EGFR has been demonstrated to contribute to cancer cell resistance to cetuximab and radiation treatment (5,6) and to be negatively correlated with overall survival of patients with multiple cancer types (7)(8)(9)(10)(11). Moreover, nuclear EGFR interacts with signal transducer and activator of transcription 3 (STAT3), signal transducer and activator of transcription 5A (STAT5A), E2F1, DNA-dependent protein kinase (DNA-PK), and proliferating cell nuclear antigen (PCNA) and plays important roles in cell transformation, proliferation, and DNA repair and replication (12)(13)(14)(15)(16). Nuclear EGFR regulates gene expression by binding to an AT-rich sequence (ATRS) of the gene's promoter (13,16,17).…”

“…Moreover, nuclear EGFR interacts with signal transducer and activator of transcription 3 (STAT3), signal transducer and activator of transcription 5A (STAT5A), E2F1, DNA-dependent protein kinase (DNA-PK), and proliferating cell nuclear antigen (PCNA) and plays important roles in cell transformation, proliferation, and DNA repair and replication (12)(13)(14)(15)(16). Nuclear EGFR regulates gene expression by binding to an AT-rich sequence (ATRS) of the gene's promoter (13,16,17). Additionally, a recent unbiased protein-DNA interactome study indicates that EGFR is a DNAbinding protein (18).…”