Anlaysis of complementary expression profiles following WT1 induction versus repression reveals the cholesterol/fatty acid synthetic pathways as a possible major target of WT1.
The Wilms' tumour suppressor gene, WT1, encodes a zinc-finger protein that is mutated in Wilms' tumours and other malignancies. WT1 is one of the earliest genes expressed during kidney development. WT1 proteins can activate and repress putative target genes in vitro, although the in vivo relevance of such target genes often remains unverified. To better understand the role of WT1 in tumorigenesis and kidney development, we need to identify downstream target genes. In this study, we have expression profiled human embryonic kidney 293 cells stably transfected to allow inducible WT1 expression and mouse mesonephric M15 cells transfected with a WT1 antisense construct to abolish endogenous expression of all WT1 isoforms to identify WT1-responsive genes. The complementary overlap between the two cell lines revealed a pronounced repression of genes involved in cholesterol biosynthesis by WT1. This pathway is transcriptionally regulated by the sterol responsive element-binding proteins (SREBPs). Here, we provide evidence that the C-terminal end of the WT1 protein can directly interact with SREBP, suggesting that WT1 may modify the transcriptional function of SREBPs via a direct protein-protein interaction. Therefore, the tumour suppressor activities of WT1 may be achieved by repressing the mevalonate pathway, thereby controlling cellular proliferation and promoting terminal differentiation.
Rae
Fiona Kaven
FK
Institute for Molecular Bioscience, Queensland Bioscience Precinct, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
Martinez
Gemma
G
Gillinder
Kevin Robert
KR
Smith
Aaron
A
Shooter
Gary
G
Forrest
Alistair Raymond
AR
Grimmond
Sean Michael
SM
Little
Melissa Helen
MH
D000818:Animals; D001665:Binding Sites; D015152:Blotting, Northern; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D003001:Cloning, Molecular; D016373:DNA, Antisense / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007668:Kidney; D008798:Mevalonic Acid / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D011994:Recombinant Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D025721:WT1 Proteins; D008798:Mevalonic Acid