Altered levels of hsromega lncRNAs further enhance Ras signaling during ectopically activated Ras induced R7 differentiation in Drosophila

AbstractWe exploited the high Ras activity induced differentiation of supernumerary R7 cells in Drosophila eyes to examine if hsrω lncRNAs influence active Ras signaling. Surprisingly, either down- or up-regulation of hsrω lncRNAs in sev-GAL4>RasV12 expressing eye discs resulted in complete pupal lethality and substantially greater increase in R7 photoreceptor number at the expense of cone cells. Enhanced nuclear p-MAPK and presence of sev-GAL4 driven RasV12 bound RafRBDFLAG in cells not expressing the sev-GAL4 driver indicated non-cell autonomous spread of Ras signaling when hsrω levels were co-altered. RNA-sequencing revealed that down-and up-regulation of hsrω transcripts in sev-GAL4>RasV12 expressing eye discs elevated transcripts of positive or negative modulators, respectively, of Ras signaling so that either condition enhances it. Altered hsrω transcript levels in sev-GAL4>RasV12 expressing discs also affected sn/sno/sca RNAs and some other RNA processing transcript levels. Post-transcriptional changes due to the disrupted intra-cellular dynamicity of omega speckle associated hnRNPs and other RNA-binding proteins that follow down- or up-regulation of hsrω lncRNAs appear to be responsible for the further elevated Ras signaling. Cell autonomous and non-autonomous enhancement of Ras signaling by lncRNAs like hsrω has implications for cell signaling during high Ras activity commonly associated with some cancers.HighlightsOur findings highlight roles of hsrω lncRNAs in conditionally modulating the important Ras signaling pathway and provide evidence for cell non-autonomous Ras signaling in Drosophila eye discs.

Download Full-text

Cell fate control in the Drosophila retina by the orphan receptor seven-up: its role in the decisions mediated by the ras signaling pathway

Development ◽

10.1242/dev.121.5.1361 ◽

1995 ◽

Vol 121 (5) ◽

pp. 1361-1372 ◽

Cited By ~ 9

Author(s):

S. Kramer ◽

S.R. West ◽

Y. Hiromi

Keyword(s):

Signaling Pathway ◽

Cell Fate ◽

Compound Eye ◽

Gene Dosage ◽

Ectopic Expression ◽

Orphan Receptor ◽

Ras Signaling ◽

Cell Type ◽

Cone Cells ◽

Ras Signaling Pathway

Drosophila seven-up is an orphan receptor of the steroid receptor family that is required to specify photoreceptor neuron subtypes in the developing compound eye. Expression of seven-up is confined to four of the eight photoreceptor precursors, R3/R4/R1/R6. We show that misexpression of seven-up in any of the other cell types within the developing ommatidium interferes with their differentiation. Each cell type responds differently to seven-up misexpression. For example, ectopic expression in the non-neuronal cone cells using the sevenless promoter/enhancer (sev-svp) causes the cone cells to take on a neuronal identity. Ectopic expression of seven-up in R2/R5 using the rough enhancer (ro-svp) causes these neurons to lose aspects of their photoreceptor subtype identity while remaining neuronal. Each cell type appears to have a different developmental time window that is sensitive to misexpressed seven-up. The temporal order of responsiveness of each cell type to misexpressed seven-up is similar but not identical to the order of neuronal differentiation. This suggests that there are processes of specification that are distinct from the specification to become a photoreceptor neuron. We have identified members of the ras signaling pathway as suppressors of the cone cell to R7 neuron transformation caused by sev-svp. Suppression of the sev-svp phenotype can be achieved by decreasing the gene-dosage of any of the members of the ras-pathway. This suggests that the function of seven-up in the cone cells requires ras signaling. However, a decrease in ras signaling results in enhancement of the phenotype caused by the ro-svp transgene. We discuss the relationship between decisions controlled by seven-up and those controlled by ras signaling.

Download Full-text

The Ras signaling pathway in Drosophila

Current Opinion in Genetics & Development ◽

10.1016/s0959-437x(95)90052-7 ◽

1995 ◽

Vol 5 (1) ◽

pp. 44-50 ◽

Cited By ~ 130

Author(s):

David A. Wassarman ◽

Marc Therrien ◽

Gerald M. Rubin

Keyword(s):

Signaling Pathway ◽

Ras Signaling ◽

Ras Signaling Pathway

Download Full-text

CD4+ T-Cell Decline after the Interruption of Antiretroviral Therapy in ACTG A5170 Is Predicted by Differential Expression of Genes in the Ras Signaling Pathway

AIDS Research and Human Retroviruses ◽

10.1089/aid.2008.0059 ◽

2008 ◽

Vol 24 (8) ◽

pp. 1047-1066 ◽

Cited By ~ 5

Author(s):

Maryanne T. Vahey ◽

Zhining Wang ◽

Zhaohui Su ◽

Martin E. Nau ◽

Amy Krambrink ◽

...

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

Differential Expression ◽

Signaling Pathway ◽

Cd4 T Cell ◽

Ras Signaling ◽

Expression Of Genes ◽

Ras Signaling Pathway ◽

Cell Decline ◽

Differential Expression Of Genes

Download Full-text

The Drosophila suppressor of sable gene encodes a polypeptide with regions similar to those of RNA-binding proteins

Molecular and Cellular Biology ◽

10.1128/mcb.11.2.894-905.1991 ◽

1991 ◽

Vol 11 (2) ◽

pp. 894-905

Author(s):

R A Voelker ◽

W Gibson ◽

J P Graves ◽

J F Sterling ◽

M T Eisenberg

Keyword(s):

Rna Processing ◽

Rna Binding ◽

Rna Binding Proteins ◽

Open Reading Frame ◽

In Vitro Translation ◽

Rna Recognition Motif ◽

Reading Frame ◽

Cdna Sequences ◽

Suppressor Of Sable

The nucleotide sequence of the Drosophila melanogaster suppressor of sable [su(s)] gene has been determined. Comparison of genomic and cDNA sequences indicates that an approximately 7,860-nucleotide primary transcript is processed into an approximately 5-kb message, expressed during all stages of the life cycle, that contains an open reading frame capable of encoding a 1,322-amino-acid protein of approximately 150 kDa. The putative protein contains an RNA recognition motif-like region and a highly charged arginine-, lysine-, serine-, aspartic or glutamic acid-rich region that is similar to a region contained in several RNA-processing proteins. In vitro translation of in vitro-transcribed RNA from a complete cDNA yields a product whose size agrees with the size predicted by the open reading frame. Antisera against su(s) fusion proteins recognize the in vitro-translated protein and detect a protein of identical size in the nuclear fractions from tissue culture cells and embryos. The protein is also present in smaller amounts in cytoplasmic fractions of embryos. That the su(s) protein has regions similar in structure to RNA-processing protein is consistent with its known role in affecting the transcript levels of those alleles that it suppresses.

Download Full-text

Abstract B18: Clostridium perfringens lethal toxin specifically targets RAS and disrupts RAS signaling pathway

10.1158/1557-3125.ras18-b18 ◽

2020 ◽

Author(s):

Maria Abreu-Blanco ◽

Ming Yi ◽

Jean-Paul Denson ◽

Matthew Holderfield

Keyword(s):

Signaling Pathway ◽

Clostridium Perfringens ◽

Lethal Toxin ◽

Ras Signaling ◽

Ras Signaling Pathway

Download Full-text

Coordination of RNA Processing Regulation by Signal Transduction Pathways

Biomolecules ◽

10.3390/biom11101475 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1475

Author(s):

Veronica Ruta ◽

Vittoria Pagliarini ◽

Claudio Sette

Keyword(s):

Gene Expression ◽

Signal Transduction ◽

Rna Processing ◽

Translational Regulation ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Signal Transduction Pathways ◽

Challenges And Opportunities ◽

Common Signal

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules.

Download Full-text

Post-transcriptional gene regulation by the RNA binding protein IGF2BP3 is critical for MLL-AF4 mediated leukemogenesis

10.1101/2020.12.20.423624 ◽

2020 ◽

Author(s):

Tiffany M Tran ◽

Julia Philipp ◽

Jaspal Bassi ◽

Neha Nibber ◽

Jolene Draper ◽

...

Keyword(s):

Rna Binding ◽

Leukemia Cell ◽

Cellular Level ◽

Ras Signaling ◽

Therapeutic Approaches ◽

Mrna Targets ◽

Ras Signaling Pathway ◽

Stem And Progenitor Cells ◽

Transcriptional Gene Regulation ◽

Poor Outcomes

ABSTRACTDespite recent advances in therapeutic approaches, patients with MLL-rearranged leukemia still have poor outcomes and a high risk of relapse. Here, we found that MLL-AF4, the most common MLL fusion protein in patients, transcriptionally induces IGF2BP3 and that IGF2BP3 strongly amplifies MLL-Af4 mediated leukemogenesis. Deletion of Igf2bp3 significantly increases the survival of mice with MLL-Af4 driven leukemia and greatly attenuates disease. At the cellular level, MLL-Af4 leukemia-initiating cells require Igf2bp3 for their function in leukemogenesis. eCLIP and transcriptome analysis of MLL-Af4 transformed stem and progenitor cells and MLL-Af4 bulk leukemia cells reveals a complex IGF2BP3-regulated post-transcriptional operon governing leukemia cell survival and proliferation. Critical mRNA targets include important leukemogenic genes such as in the Hoxa locus and numerous genes within the Ras signaling pathway. Together, our findings show that IGF2BP3 is an essential positive regulator of MLL-AF4 mediated leukemogenesis and is a potential therapeutic target in this disease.

Download Full-text