Abstract 3089: Regulation of GFI proteins by Notch intracellular domains
| العنوان: | Abstract 3089: Regulation of GFI proteins by Notch intracellular domains |
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| المؤلفون: | Daniel Andrade, Ryan Quinton, Jason Singer, Diana Bareyan, Michael E. Engel |
| المصدر: | Cancer Research. 72:3089-3089 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Zinc finger, Genetics, Cancer Research, Growth factor, medicine.medical_treatment, SUMO protein, Hematopoietic stem cell, Biology, Cell fate determination, Transactivation, Haematopoiesis, medicine.anatomical_structure, Oncology, medicine, Ankyrin repeat |
| الوصف: | Growth factor independence (GFI)-1 and its homolog, GFI1B, are transcriptional regulators that play critical roles during hematopoiesis. GFI family proteins are characterized by near-invariant SNAG and zinc finger domains that direct transcriptional repression and DNA-binding, respectively. A linker region with limited homology and unknown function separates the conserved SNAG and zinc-finger regions. GFI proteins display distinct expression patterns within the myelo-erythroid compartment and make similarly distinct contributions to cell fate specification. GFI1 expression is necessary for hematopoietic stem cell maintenance and is required for granulocytic differentiation beyond the promyelocyte stage. Enforced expression of GFI1 promotes IL-2-independent growth of hematopoietic progenitors and inhibits apoptosis. Mutations in GFI1 lead to a severe congenital neutropenia syndrome that carries an increased risk of myeloid leukemia development. GFI1B expression predominates in erythroid and megakaryocytic precursors and is required for terminal differentiation along both lineages. Moreover, elevated GFI1B expression occurs preferentially in erythroid and megakaryoblastic leukemias, and contributes to the malignant phenotype by supporting growth and preventing apoptosis. Given their complementary roles as growth and survival factors, yet distinct contributions to lineage allocation in hematopoiesis, it is essential to define how GFI family proteins are integrated into the signaling machinery governing cell fate specification. We show that both GFI1 and GFI1B interact with intracellular domains of Notch receptors. Enforced expression of the Notch1 intracellular domain (N1-ICD) impairs GFI-mediated transcriptional repression. Using deletion mutagenesis, we have mapped the regions required for the N1-ICD–GFI1 interaction. Both the ankyrin repeat and transactivation domains of N1-ICD contribute binding surfaces for GFI1. In reciprocal mapping experiments, we show that N1-ICD binding to GFI1 requires a 128-amino acid motif in the divergent linker region near the zinc finger repeat elements. This region contains a high probability consensus sumoylation element that is absolutely conserved in mammalian species but not present in GFI1B. These data suggest that Notch activation may directly impact transcriptional targets regulated by GFI family proteins and expand the potential sphere of influence for Notch in hematopoietic development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3089. doi:1538-7445.AM2012-3089 |
| تدمد: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2012-3089 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::dd2ac63ffbf5019b32c4bc86189fc549 https://doi.org/10.1158/1538-7445.am2012-3089 |
| رقم الانضمام: | edsair.doi...........dd2ac63ffbf5019b32c4bc86189fc549 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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| DOI: | 10.1158/1538-7445.am2012-3089 |