Signal transducer and activator of transcription 5 as a key signaling pathway in normal mammary gland developmental biology and breast cancer

Furth, Priscilla A.; Nakles, Rebecca E.; Millman, Sarah L.; Díaz-Cruz, Edgar S.; Cabrera, M. Carla

doi:10.1186/bcr2921

Cited by 93 publications

(80 citation statements)

References 98 publications

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“…Female-specific lincRNAs also showed significant enrichment for female-biased binding by STAT5 and FOXA2, which are proposed to activate transcription of the bound female-spe-cific lincRNAs. Of note, only 7 of the 171 GH-regulated sex-specific lincRNAs were expressed in other tissues with high STAT5 activity, i.e., T cells and mammary gland (115,116), indicating that STAT5 activity alone is not sufficient to drive expression of these genes (data not shown). Two of the 7 coexpressed lincRNAs have a nearby STAT5 binding site in the liver: LiverLincs_chr14_3799 (expressed in mammary gland, regulatory T cells [Tregs], and Th2 cells but not Th1 cells) and LiverLincs_ chr6_1886 (expressed in all three T cell subtypes).…”

Section: Discussionmentioning

confidence: 99%

Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone

Melia

Hao

Yilmaz

et al. 2016

Molecular and Cellular Biology

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Long intergenic noncoding RNAs (lincRNAs) are increasingly recognized as key chromatin regulators, yet few studies have characterized lincRNAs in a single tissue under diverse conditions. Here, we analyzed 45 mouse liver RNA sequencing (RNA-Seq) data sets collected under diverse conditions to systematically characterize 4,961 liver lincRNAs, 59% of them novel, with regard to gene structures, species conservation, chromatin accessibility, transcription factor binding, and epigenetic states. To investigate the potential for functionality, we focused on the responses of the liver lincRNAs to growth hormone stimulation, which imparts clinically relevant sex differences to hepatic metabolism and liver disease susceptibility. Sex-biased expression characterized 247 liver lincRNAs, with many being nuclear RNA enriched and regulated by growth hormone. The sex-biased lincRNA genes are enriched for nearby and correspondingly sex-biased accessible chromatin regions, as well as sex-biased binding sites for growth hormone-regulated transcriptional activators (STAT5, hepatocyte nuclear factor 6 [HNF6], FOXA1, and FOXA2) and transcriptional repressors (CUX2 and BCL6). Repression of female-specific lincRNAs in male liver, but not that of male-specific lincRNAs in female liver, was associated with enrichment of H3K27me3-associated inactive states and poised (bivalent) enhancer states. Strikingly, we found that liver-specific lincRNA gene promoters are more highly species conserved and have a significantly higher frequency of proximal binding by liver transcription factors than liver-specific protein-coding gene promoters. Orthologs for many liver lincRNAs were identified in one or more supraprimates, including two rat lincRNAs showing the same growth hormone-regulated, sex-biased expression as their mouse counterparts. This integrative analysis of liver lincRNA chromatin states, transcription factor occupancy, and growth hormone regulation provides novel insights into the expression of sexspecific lincRNAs and their potential for regulation of sex differences in liver physiology and disease. High-throughput sequencing of mammalian transcriptomes has revealed nearly ubiquitous transcription of the genome and the generation of large numbers of noncoding transcripts. Noncoding RNAs (ncRNAs) have drawn much attention as potential chromatin regulators, exemplified by classical ncRNAs, such as Xist (1). Several thousand ncRNAs have been discovered in human (2, 3), mouse (4-7), zebrafish (8,9), and fruit fly (10,11). Individual ncRNAs were shown to play diverse regulatory roles in gene expression (9,(12)(13)(14)(15); however, the vast majority of ncRNAs are poorly characterized, both computationally and experimentally. Many ncRNAs share salient features of protein-coding genes, including transcription by RNA polymerase II, 5= capping, splicing, polyadenylation, and deposition of histone marks associated with transcription, specifically H3K4me3 at the promoter and H3K36me3 across the gene body (4). These ncRNAs are typically Ͼ200 nucleo...

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Section: Discussionmentioning

confidence: 99%

Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone

Melia

Hao

Yilmaz

et al. 2016

Molecular and Cellular Biology

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“…In contrast to that of JAK1/2, the phosphorylation level of STAT5A was significantly reduced. STAT5A is primarily activated by growth factors, such as prolactin (66). Further studies are required to understand how these pathways are regulated during primary KSHV infection.…”

Section: Figmentioning

confidence: 99%

Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

Cheng

Sawant

Lan

et al. 2015

J Virol

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Viruses often hijack cellular pathways to facilitate infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is IMPORTANCEKaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. Through genome-wide kinase screening, we found that KSHV activates the MSK1/2-CREB1 pathway during primary infection and that it depends on this pathway for viral lytic replication. Inhibition of this pathway blocks KSHV lytic replication. These results illustrate a mechanism by which KSHV hijacks a cellular pathway for its replication, and they identify a potential therapeutic target. V iruses depend on cell signaling pathways for successful infection and replication. Identification of pathways hijacked by viruses not only reveals the mechanisms of infection and replication of these viruses but also provides novel therapeutic targets. Kaposi's sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus etiologically associated with Kaposi's sarcoma (KS), a vascular tumor of endothelial cells commonly found in AIDS patients, and with two B-cell lymphoproliferative diseases, namely, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD) (1-3). The early phase of primary KSHV infection is a highly regulated multistep event consisting of virion attachment and binding, membrane fusion, internalization, intracellular trafficking, and early viral gene expression (4). KSHV infection induces phosphorylation of cellular proteins, leading to the activation of signal transduction pathways. A number of these pathways regulate KSHV entry, trafficking, and viral gene expression (4). Binding of KSHV glycoproteins to cellular receptors activates focal adhesion kinase (FAK), Src, phosphatidylinositol-3-kinases (PI3Ks), and mitogen-activated protein kinases (MAPKs), including MEK/extracellular signal-regulated kinase (MEK/ERK), p38, and Jun N-terminal kinase (JNK), facilitating KSHV internalization and trafficking (5-10). This process depends on rearrangements of the actin and microtubule cytoskeletons and on factors, such as Rho-GTPases and diaphanous-2 (Dia-2), that regulate their dynamics (8, 11). KSHV entry and trafficking rely on the dynamics of the ubiquitin/proteasome system and on activation of the E3 ligase c-Cbl to maintain the endosomal activities and cellular signaling (12, 13).Successful KSHV infection requires the coordinated expres-

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“…Increasing prolactin levels during pregnancy result in Stat5 activation through binding to Prlr, activation of Jak2, and Jak2-directed Stat5 phosphorylation (Furth et al 2011). However, Stat5 phosphorylation can also occur downstream from pathways other than Prlr.…”

Section: Akt-induced Mammary Differentiation Requires Prlr and Stat5a/bmentioning

confidence: 99%

Autocrine prolactin induced by the Pten–Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways

et al. 2012

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Extrapituitary prolactin (Prl) is produced in humans and rodents; however, little is known about its in vivo regulation or physiological function. We now report that autocrine prolactin is required for terminal mammary epithelial differentiation during pregnancy and that its production is regulated by the Pten-PI3K-Akt pathway. Conditional activation of the PI3K-Akt pathway in the mammary glands of virgin mice by either Akt1 expression or Pten deletion rapidly induced terminal mammary epithelial differentiation accompanied by the synthesis of milk despite the absence of lobuloalveolar development. Surprisingly, we found that mammary differentiation was due to the PI3K-Akt-dependent synthesis and secretion of autocrine prolactin and downstream activation of the prolactin receptor (Prlr)-Jak-Stat5 pathway. Consistent with this, Akt-induced mammary differentiation was abrogated in Prl -/-mice. Furthermore, cells treated with conditioned medium from mammary glands in which Akt had been activated underwent rapid Stat5 phosphorylation in a manner that was blocked by inhibition of Jak2, treatment with an anti-Prl antibody, or deletion of the prolactin gene. Demonstrating a physiological requirement for autocrine prolactin, mammary glands from lactation-defective Akt1 -/-;Akt2 +/-mice failed to express autocrine prolactin or activate Stat5 during late pregnancy despite normal levels of circulating serum prolactin and pituitary prolactin production. Our findings reveal that PI3K-Akt pathway activation is necessary and sufficient to induce autocrine prolactin production in the mammary gland, Stat5 activation, and terminal mammary epithelial differentiation, even in the absence of the normal developmental program that prepares the mammary gland for lactation. Together, these findings identify a function for autocrine prolactin during normal development and demonstrate its endogenous regulation by the PI3K-Akt pathway.

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Signal transducer and activator of transcription 5 as a key signaling pathway in normal mammary gland developmental biology and breast cancer

Cited by 93 publications

References 98 publications

Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone

Hepatic Long Intergenic Noncoding RNAs: High Promoter Conservation and Dynamic, Sex-Dependent Transcriptional Regulation by Growth Hormone

Screening of the Human Kinome Identifies MSK1/2-CREB1 as an Essential Pathway Mediating Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication during Primary Infection

Autocrine prolactin induced by the Pten–Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways

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