The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi.
The Wilms' tumor suppressor protein WT1 functions as a transcriptional regulator of genes controlling growth, apoptosis, and differentiation. It has become clear that WT1 can act as an oncogene in many tumors, primarily through the inhibition of apoptosis. Here, we identify the serine protease HtrA2 as a WT1 binding partner and find that it cleaves WT1 at multiple sites following the treatment of cells with cytotoxic drugs. Ablation of HtrA2 activity either by chemical inhibitor or by siRNA prevents the proteolysis of WT1 under apoptotic conditions. Moreover, the apoptosis-dependent cleavage of WT1 is defective in HtrA2 knockout cells. Proteolysis of WT1 by HtrA2 causes the removal of WT1 from its binding sites at gene promoters, leading to alterations in gene regulation that enhance apoptosis. Our findings provide insights into the function of HtrA2 in the regulation of apoptosis and the oncogenic activities of WT1.
Hartkamp
Jörg
J
Faculty of Life Sciences, The Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Carpenter
Brian
B
Roberts
Stefan G E
SG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D005786:Gene Expression Regulation; D006367:HeLa Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D051379:Mice; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology*; D025721:WT1 Proteins / Q000378:metabolism*
D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; D025721:WT1 Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse