thesis

The role of Wilms’ Tumor gene product (WT1)in CD95-mediated apoptosis in T-cell leukaemias

Abstract

Abstract Apoptosis, also known as programmed cell death, is a very critical process for the maintenance of tissue homeostasis in multicellular organisms. In our immune system, which is comprised of different cell types with different but interconnected functions, apoptosis plays a crucial role in preserving homeostasis during development, throughout adult life and upon termination of immune responses. Any defects in apoptosis can potentially lead to autoimmunity or cancer. CD95 (Fas/APO-1) belongs to the family of the so-called death receptors, and upon binding with its ligand, the CD95L, can instruct CD95-bearing cells to undergo apoptosis. The CD95/CD95L system is crucial for homeostasis of the immune system, and deregulation of CD95-mediated apoptosis results in several diseases including autoimmune syndromes, leukaemias or AIDS. CD95-mediated apoptosis is used by the T-lymphocytes of the immune system at several stages during their development and after the termination of an immune response, so that the quality and quantity of activated T cells are controlled. In these cases, the T cells being activated through their TCR die via CD95-mediated apoptosis upon restimulation, a process collectively known as activation-induced cell death (AICD). One characteristic of cancer is its resistance to apoptosis. Leukaemias are no exception. One of the ways a cancerous T-lymphocyte evades death is by deregulating its CD95/CD95L system by e.g., downregulating the CD95L. NF-AT and Egr proteins (1-3) are amongst the different transcription factors that take part in the regulation of the CD95L. Upon TCR stimulation different signalling pathways lead to the activation of NF-AT and the transcriptional activation of Egr factors. These then bind on the CD95L promoter and activate it. Wilms’ tumor gene 1 (WT1) encodes a four-zinc-finger protein. Alternative splicing at the pre-mRNA level yields several transcript variants, of which the best characterized are the so called WT1-KTS and WT1+KTS isoforms. The WT1-KTS isoform, which lacks three amino acids between zinc-fingers three and four, is suggested to be a transcription factor that belongs to the Egr family and has target sequences similar to Egr1. WT1 is expressed during the early stages of haematopoiesis and has been implicated in leukaemogenesis. Its role in leukaemias is controversial as it is either found to be mutated or overexpressed, and overexpression is linked with more immature leukaemias. It is therefore uncertain whether WT1 is a tumor suppressor or tumor promoter. It was threfore of interest to analyze the expression of WT1 in T cell leukaemias and understand its role in CD95-mediated apoptosis

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