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Functional Significance of Cytoplasmic WT1


The Wilms' tumour suppressor, WT1, is a multifunctional zinc finger protein that was shown to be essential for development of the genitourinary system and some other mesodermally derived tissues. Mutations in the WT1 gene are implicated in a number of developmental syndromes and some types of malignancies in humans. WT1 is a multifunctional transcription factor that both activates and represses GC-rich promoters. It was suggested that WT1 activates genes of the epithelial lineage, and acts as a transcriptional repressor of genes involved in mesenchymal cell proliferation.

Mammalian WT1 gene encodes about 24 different protein isoforms whereas other vertebrates have only 2 isoforms that differ by the insertion of 3 amino acids (+/- KTS). Besides its well-known function in transcription regulation, work mainly from Professor Hastie's laboratory has led to the suggestion that WT1 takes part in post-transcriptional processes such as RNA splicing (Larsson et al., Cell 5: 391-401, 1995; Davies et al., Genes Dev. 15: 3217-3225, 1998; Hastie, Cell 106: 391-394, 2001). Recently Professor Hastie's group showed that WT1 shuttles between nucleus and cytoplasm; and what was even more astonishing - WT1 was found on functional polysomes (Niksic et al., Hum. Mol. Genet. 15: 463-471, 2004). Also they identified novel sites of WT1 expression, including the pituitary gland, pancreas and some neurons. In all these cases WT1 appears to be almost entirely localized in the cytoplasm.

These findings raise questions about possible new roles for WT1 in regulation of expression not only at the levels of transcription and splicing but also transport and translation. The theme became the cutting edge in the field of WT1 biology and general laws of regulation of expression at different levels. Thus the main goal of this proposal is to investigate the possible roles of WT1 in regulating RNA transport, translation or other cytoplasmic processes in the context of development and physiology.

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