Biomedical subjects

Ilaria Rebay

Publications and source records attributed to Ilaria Rebay.

23 records · Page 2Linked to original sources

PubMed2003

CRM1-mediated nuclear export and regulated activity of the Receptor Tyrosine Kinase antagonist YAN require specific interactions with MAE.

ETS family transcription factors serve as downstream effectors of signal transduction pathways, mediating cellular proliferation, differentiation and, when misregulated, tumorigenesis. The transcriptional repressor YAN prevents inappropriate responses to Receptor Tyrosine Kinase signaling by outcompeting POINTED for access to target gene promoters. We demonstrate that the molecular mechanism underlying downregulation of YAN involves CRM1-mediated nuclear export and define a novel role in this context for MAE, a co-factor previously implicated in facilitating MAPK phosphorylation of YAN. In addition to promoting YAN downregulation, MAE also participates in an inhibitory feedback loop that attenuates POINTED-P2 activation. Thus, we propose that MAE plays multiple independent roles in fine-tuning the levels of POINTED and YAN activity in accordance with changing RTK signaling conditions.

Active Transport, Cell Nucleus↗

PubMed2003

Splits ends is a tissue/promoter specific regulator of Wingless signaling.

Wingless directs many developmental processes in Drosophila by regulating expression of specific target genes through a conserved signaling pathway. Although many nuclear factors have been implicated in mediating Wingless-induced transcription, the mechanism of how Wingless regulates different targets in different tissues remains poorly understood. We report here that the split ends gene is required for Wingless signaling in the eye, wing and leg imaginal discs. Expression of a dominant-negative version of split ends resulted in more dramatic reductions in Wingless signaling than split ends-null alleles, suggesting that it may have a redundant partner. However, removal of split ends or expression of the dominant-negative had no effect on several Wingless signaling readouts in the embryo. The expression pattern of Split ends cannot explain this tissue-specific requirement, as the protein is predominantly nuclear and present throughout embryogenesis and larval tissues. Consistent with its nuclear location, the split ends dominant-negative acts downstream of Armadillo stabilization. Our data indicate that Split ends is an important positive regulator of Wingless signaling in larval tissues. However, it has no detectable role in the embryonic Wingless pathway, suggesting that it is a tissue or promoter-specific factor.

Alleles↗

PubMed2002

Biological functions of the ISWI chromatin remodeling complex NURF.

The nucleosome remodeling factor (NURF) is one of several ISWI-containing protein complexes that catalyze ATP-dependent nucleosome sliding and facilitate transcription of chromatin in vitro. To establish the physiological requirements of NURF, and to distinguish NURF genetically from other ISWI-containing complexes, we isolated mutations in the gene encoding the large NURF subunit, nurf301. We confirm that NURF is required for transcription activation in vivo. In animals lacking NURF301, heat-shock transcription factor binding to and transcription of the hsp70 and hsp26 genes are impaired. Additionally, we show that NURF is required for homeotic gene expression. Consistent with this, nurf301 mutants recapitulate the phenotypes of Enhancer of bithorax, a positive regulator of the Bithorax-Complex previously localized to the same genetic interval. Finally, mutants in NURF subunits exhibit neoplastic transformation of larval blood cells that causes melanotic tumors to form.

Adenosine Triphosphatases↗

PubMed2002

Keeping the receptor tyrosine kinase signaling pathway in check: lessons from Drosophila.

The receptor tyrosine kinase (RTK) signaling network plays a central role in regulating cellular differentiation, proliferation, and survival in all metazoan animals. Excessive or continuous activation of the RTK pathway has been linked to carcinogenesis in mammals, underscoring the importance of preventing uncontrolled signaling. This review will focus on the inhibitory mechanisms that keep RTK-mediated signals in check, with emphasis on conserved principles discerned from studies using Drosophila as a model system. Two general strategies of inhibition will be discussed. The first, threshold regulation, postulates that an effective way of antagonizing RTK signaling is to erect and maintain high threshold barriers that prevent inappropriate responses to moderate signaling levels. Activation of the pathway above this level overcomes the inhibitory blocks and shifts the balance to allow a positive flow of inductive information. A second layer of negative regulation involving induction of negative feedback loops that limit the extent, strength, or duration of the signal prevents runaway signaling in response to the high levels of activation required to surmount the threshold barriers. Such autoinhibitory mechanisms attenuate signaling at critical points throughout the network, from the receptor to the downstream effectors.

Animals↗

PubMedDate not supplied

Signal integration during development: mechanisms of EGFR and Notch pathway function and cross-talk.

Metazoan development relies on a highly regulated network of interactions between conserved signal transduction pathways to coordinate all aspects of cell fate specification, differentiation, and growth. In this review, we discuss the intricate interplay between the epidermal growth factor receptor (EGFR; Drosophila EGFR/DER) and the Notch signaling pathways as a paradigm for signal integration during development. First, we describe the current state of understanding of the molecular architecture of the EGFR and Notch signaling pathways that has resulted from synergistic studies in vertebrate, invertebrate, and cultured cell model systems. Then, focusing specifically on the Drosophila eye, we discuss how cooperative, sequential, and antagonistic relationships between these pathways mediate the spatially and temporally regulated processes that generate this sensory organ. The common themes underlying the coordination of the EGFR and Notch pathways appear to be broadly conserved and should, therefore, be directly applicable to elucidating mechanisms of information integration and signaling specificity in vertebrate systems.

Amyloid Precursor Protein Secretases↗