Regulation of gene expression by WT1 in development and tumorigenesis.
WT1 encodes a zinc finger transcription factor implicated in normal development and tumorigenesis. Germline mutation or deletion of WT1 results in a spectrum of abnormal kidney development, male-to-female intersex disorders, and predisposition to pediatric nephroblastoma, Wilms tumor. Initially thought to encode a transcriptional repressor, WT1-dependent functions are now more clearly linked to its property as a transcriptional activator of genes involved in renal development and sex determination. WT1 is expressed in 4 isoforms as a result of 2 alternative messenger RNA splicing events, the more significant of which encodes the 3 amino acids lysine, threonine, and serine (KTS) between zinc fingers 3 and 4. Although WT1 isoforms lacking KTS act as sequence-specific DNA binding factors, a large body of evidence now implicates the KTS-containing isoforms in RNA processing. In keeping with distinct biochemical mechanisms for these isoforms, genetic data from humans and mice point to separate but partially overlapping roles for WT1 (+KTS) and (-KTS) during genitourinary development. Recently, a hematopoietic model system has been used to study functional properties of WT1 in vitro. WT1 expression in primary hematopoietic cells leads to stage-specific effects that may be relevant to WT1-mediated tumor suppression.
Ellisen
Leif W
LW
Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA. lellisen@partners.org
D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D006410:Hematopoiesis; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D025721:WT1 Proteins / Q000235:genetics / Q000502:physiology*; D009396:Wilms Tumor / Q000209:etiology* / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; D025721:WT1 Proteins