Gene amplification and associated loss of 5' regulatory sequences of CoAA in human cancers.
CoAA is an RRM-containing transcriptional coactivator that stimulates transcriptional activation and regulates alternative splicing. We show that the CoAA gene is amplified at the chromosome 11q13 locus in a subset of primary human cancers including non-small cell lung carcinoma, squamous cell skin carcinoma and lymphoma. Analysis of 42 primary tumors suggests that CoAA amplifies independently from the CCND1 locus. Detailed mapping of three CoAA amplicons reveals that the amplified CoAA gene is consistently located at the 5' boundaries of the amplicons. The CoAA coding and basal promoter sequences are retained within the amplicons but upstream silencing sequences are lost. CoAA protein is overexpressed in tumors containing the amplified CoAA gene. RNA dot blot analysis of 100 cases of primary tumors suggests elevated CoAA mRNA expression. CoAA positively regulates its own basal promoter in transfection assays. Thus, gene amplification, loss of silencing sequence and positive feedback regulation may lead to drastic upregulation of CoAA protein. CoAA has transforming activities when tested in soft agar assays, and CoAA is homologous to oncoproteins EWS and TLS, which regulate alternative splicing. These data imply that CoAA may share a similar oncogenic mechanism with oncogene EWS and that CoAA deregulation may alter the alternative splicing of target genes.
Sui
Y
Y
Department of Pathology, Medical College of Georgia, Augusta, GA 30912, USA.
Yang
Z
Z
Xiong
S
S
Zhang
L
L
Blanchard
K L
KL
Peiper
S C
SC
Dynan
W S
WS
Tuan
D
D
Ko
L
L
D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics; D005784:Gene Amplification / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D000882:Haplorhini; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D015854:Up-Regulation
D056741:Cyclin D; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; C436317:RBM14 protein, human; D012333:RNA, Messenger