Dichterbij : over regionalisering van voedselketens en een grotere rol voor de consument

Vier modellen die alternatieven bieden voor de huidige organisatie van voedselproductie en landschap. Ze hebben als kenmerk dat er sprake is van een andere positie van de burger en consumen

Molecular Mechanisms in Differentiation - Induction in Acute Promyelocytic Leukemia.

Contains fulltext : 70517.pdf (publisher's version ) (Open Access)Leukemia is a hematological malignancy that is characterized by the clonal expansion of immature hematopoietic cells, which have escaped from the tightly coordinated cell cycle regulation, differentiation and apoptosis controls. In general, leukemia is characterized by a variety of mutations in pathways that are required for normal hematopoiesis. This thesis describes target genes of the mutated transcription factor PML-RAR , which is expressed in acute promyelocytic leukemia (APL) cells. APL, which accounts for 5-10% of all acute myeloid leukemias (AMLs), represents the best prognostic group amongst the different forms of leukemia having the highest curability. APL requires a unique form of treatment, which constitutes the first successful form of leukemia therapy that is based on induction of differentiation of the malignant cells, using all-trans retinoic acid (ATRA). The addition of pharmacological doses of ATRA to standard chemotherapy has led to an improvement of cure rates from 40% with chemotherapy alone to up to 90% when combined with ATRA. The identification of the chromosomal translocation t(15;17), which causes the expression of the chimeric oncoprotein PML-RAR and which is the genetic hallmark of APL, is important to establish the diagnosis. ATRA has been proven to directly target the product of this molecular defect and the APL model provides an example of targeted therapy based on differentiation induction. In this thesis we describe the identification of three ATRA-responsive genes in APL cells that are transcriptionally regulated by PML-RAR via a novel mechanism. Their biological function and their mechanism of action were studied in more detail in APL cellsRU Radboud Universiteit Nijmegen, 17 januari 2008Promotor : Witte, T.J.M. de Co-promotores : Jansen, J.H., Reijden, B.A. van der159 p

Retinoic acid-dependent gene transactivation by PML-RAR without direct DNA-binding.

Contains fulltext : 48087.pdf (publisher's version ) (Open Access

Gene transactivation without direct DNAbinding defines a novel gain-of-function for PML-RARα

PML-RARα is the causative oncogene in 5% to 10% of the cases of acute myeloid leukemia. At physiological concentrations of retinoic acid, PML-RARα silences RARα target genes, blocking differentiation of the cells. At high concentrations of ligand, it (re)activates the transcription of target genes, forcing terminal differentiation. The study of RARα target genes that mediate this differentiation has identified several genes that are important for proliferation and differentiation control in normal and malignant hematopoietic cells. In this paper, we show that the PML-RARα fusion protein not only interferes with the transcription of regular RARα target genes. We show that the ID1 and ID2 promoters are activated by PML-RARα but, unexpectedly, not by wildtype RARα/RXR. Our data support a model in which the PML-RARα fusion protein regulates a novel class of target genes by interaction with the Sp1 and NF-Y transcription factors, without directly binding to the DNA, defining a gain-of-function for the oncoprotein

The ubiquitin ligase Triad1 inhibits myelopoiesis through UbcH7 and Ubc13 interacting domains.

Contains fulltext : 81145.pdf (publisher's version ) (Closed access)Ubiquitination plays a major role in many aspects of hematopoiesis. Alterations in ubiquitination have been implicated in hematological cancer. The ubiquitin ligase Triad1 controls the proliferation of myeloid cells. Here, we show that two RING (really interesting new gene) domains in Triad1 differentially bind ubiquitin-conjugating enzymes, UbcH7 and Ubc13. UbcH7 and Ubc13 are known to catalyze the formation of different poly-ubiquitin chains. These chains mark proteins for proteasomal degradation or serve crucial non-proteolytic functions, respectively. In line with the dual Ubc interactions, we observed that Triad1 catalyzes the formation of both types of ubiquitin chains. The biological relevance of this finding was studied by testing Triad1 mutants in myeloid clonogenic assays. Full-length Triad1 and three mutants lacking conserved domains inhibited myeloid colony formation by over 50%. Strikingly, deletion of either RING finger completely abrogated the inhibitory effect of Triad1 in clonogenic growth. We conclude that Triad1 exhibits dual ubiquitin ligase activity and that both of its RING domains are crucial to inhibit myeloid cell proliferation. The differential interaction of the RINGs with Ubcs strongly suggests that the ubiquitination mediated through UbcH7 as well as Ubc13 plays a major role in myelopoiesis.10 p