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Abstract
The E2F and MYC transcription factors are critical regulators of cell proliferation and contribute to the development of human cancers. Here, we report on the identification of a novel E2F target gene, ATAD2, the predicted protein product of which contains both a bromodomain and an ATPase domain. The pRB-E2F pathway regulates ATAD2 expression, which is limiting for the entry into the S phase of the cell cycle. We show that ATAD2 binds the MYC oncogene and stimulates its transcriptional activity. ATAD2 maps to chromosome 8q24, 4.3 Mb distal to MYC, in a region that is frequently found amplified in cancer. Consistent with this, we show that ATAD2 expression is high in several human tumors and that the expression levels correlate with clinical outcome of breast cancer patients. We suggest that ATAD2 links the E2F and MYC pathways and contributes to the development of aggressive cancer through the enhancement of MYC-dependent transcription.
Highlights
The retinoblastoma protein pathway has a central role in the control of cell proliferation [1]
By combining gene expression profiles done in our lab and publicly available databases (Supplementary Fig. S2), we identified a new E2F target gene, ATAD2, which is predicted to be overexpressed and amplified in human cancer
We have shown that ATAD2 is expressed at high levels in a significant proportion of human tumors, but not in benign lesions or normal tissues
Summary
The retinoblastoma protein (pRB) pathway has a central role in the control of cell proliferation [1]. Most human cancers harbor mutations in core members of the pRB pathway, and as a consequence, E2F-regulated genes are aberrantly expressed. E2F target genes such as MYC, CCNE1 (cyclin E1), B-MYB, c-MYB, and EZH2 are bona fide oncogenes, frequently amplified and overexpressed in primary human tumors [2,3,4,5]. MYC is one of the most studied oncogenes, which contributes to the malignancy of many different aggressive and undifferentiated human cancers [4]. The pathologic effect of MYC has been ascribed to its ability to control many cellular processes such as cell growth, differentiation, apoptosis, and, more recently, DNA damage response, genomic instability, angiogenesis, and tumor invasiveness [6]. MYC acts as a potent, sequence-specific transcription factor [6] interacting both with the SWI/SNF chromatin remodeling complexes [7] and with the histone acetyltransferases CBP/p300 [8], GCN5 [9, 10], and TIP60 [11]
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