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Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells.

ABSTRACT: The serine-threonine kinase AKT1 plays essential roles during normal mammary gland development as well as the initiation and progression of breast cancer. AKT1 is generally considered a ubiquitously expressed gene, and its persistent activation is transcriptionally controlled by regulatory elements characteristic of housekeeping gene promoters. We recently identified a novel Akt1 transcript in mice (Akt1m), which is induced by growth factors and their signal transducers of transcription from a previously unknown promoter. The purpose of this study was to examine whether normal and neoplastic human breast epithelial cells express an orthologous AKT1m transcript and whether its expression is deregulated in cancer cells.Initial sequence analyses were performed using the UCSC Genome Browser and GenBank to assess the potential occurrence of an AKT1m transcript variant in human cells and to identify conserved promoter sequences that are orthologous to the murine Akt1m. Quantitative RT-PCR was used to determine the transcriptional activation of AKT1m in mouse mammary tumors as well as 41 normal and neoplastic human breast epithelial cell lines and selected primary breast cancers.We identified four new AKT1 transcript variants in human breast cancer cells that are orthologous to the murine Akt1m and that encode the full-length kinase. These transcripts originate from an alternative promoter that is conserved between humans and mice. Akt1m is upregulated in the majority of luminal-type and basal-type mammary cancers in four different genetically engineered mouse models. Similarly, a subset of human breast cancer cell lines and primary breast cancers exhibited a higher expression of orthologous AKT1m transcripts.The existence of an alternative promoter that drives the expression of the unique AKT1m transcript may provide a mechanism by which the levels of AKT1 can be temporally and spatially regulated at particular physiological states, such as cancer, where a heightened activity of this kinase is required.

SUBMITTER: Schmidt JW

PROVIDER: S-EPMC4068023 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells.

Schmidt Jeffrey W JW Wehde Barbara L BL Sakamoto Kazuhito K Triplett Aleata A AA West William W WW Wagner Kay-Uwe KU

BMC cancer 20140315

<h4>Background</h4>The serine-threonine kinase AKT1 plays essential roles during normal mammary gland development as well as the initiation and progression of breast cancer. AKT1 is generally considered a ubiquitously expressed gene, and its persistent activation is transcriptionally controlled by regulatory elements characteristic of housekeeping gene promoters. We recently identified a novel Akt1 transcript in mice (Akt1m), which is induced by growth factors and their signal transducers of tra ...[more]

PMID: 24628780

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Project description:Expression of the human cytomegalovirus (HCMV) IE1 and IE2 proteins is critical for the establishment of lytic infection and reactivation from viral latency. Defining the mechanisms controlling IE1 and IE2 expression is therefore important for understanding how HCMV regulates its replicative cycle. Here we identify several novel transcripts encoding full-length IE1 and IE2 proteins during HCMV lytic replication. Two of the alternative major immediate early (MIE) transcripts initiate in the first intron, intron A, of the previously defined MIE transcript, while others extend the 5' untranslated region. Each of the MIE transcripts associates with polyribosomes in infected cells and therefore contributes to IE1 and IE2 protein levels. Surprisingly, deletion of the core promoter region of the major immediate early promoter (MIEP) from a plasmid containing the MIE genomic locus did not completely abrogate IE1 and IE2 expression. Instead, deletion of the MIEP core promoter resulted in increased expression of alternative MIE transcripts, suggesting that the MIEP suppresses the activity of the alternative MIE promoters. While the canonical MIE mRNA was the most abundant transcript at immediate early times, the novel MIE transcripts accumulated to levels equivalent to that of the known MIE transcript later in infection. Using two HCMV recombinants, we found that sequences in intron A of the previously defined MIE transcript are required for efficient IE1 and IE2 expression and viral replication. Together, our results identify new regulatory sequences controlling IE1 and IE2 expression and suggest that multiple transcription units act in concert to regulate IE1 and IE2 expression during lytic infection.The HCMV IE1 and IE2 proteins are critical regulators of HCMV replication, both during primary infection and reactivation from viral latency. This study expands our understanding of the sequences controlling IE1 and IE2 expression by defining novel transcriptional units controlling the expression of full-length IE1 and IE2 proteins. Our results suggest that alternative promoters may allow for IE1 and IE2 expression when MIEP activity is limiting, as occurs in latently infected cells.

Dataset Information

Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells.

Publications

Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells.

Similar Datasets

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