-
Alberto C Vitari,
Kevin G Leong,
Kim Newton,
Cindy Yee,
Karen O'Rourke,
Jinfeng Liu,
Lilian Phu,
Rajesh Vij, Ronald Ferrando,
Suzana S Couto,
Sankar Mohan,
Ajay Pandita,
Jo-Anne Hongo,
David Arnott,
Ingrid E Wertz,
Wei-Qiang Gao,
Dorothy M French,
Vishva M Dixit
[show abstract]
[hide abstract]
ABSTRACT: The proto-oncogenes ETV1, ETV4 and ETV5 encode transcription factors in the E26 transformation-specific (ETS) family, which includes the most frequently rearranged and overexpressed genes in prostate cancer. Despite being critical regulators of development, little is known about their post-translational regulation. Here we identify the ubiquitin ligase COP1 (also known as RFWD2) as a tumour suppressor that negatively regulates ETV1, ETV4 and ETV5. ETV1, which is mutated in prostate cancer more often, was degraded after being ubiquitinated by COP1. Truncated ETV1 encoded by prostate cancer translocation TMPRSS2:ETV1 lacks the critical COP1 binding motifs and was 50-fold more stable than wild-type ETV1. Almost all patient translocations render ETV1 insensitive to COP1, implying that this confers a selective advantage to prostate epithelial cells. Indeed, COP1 deficiency in mouse prostate elevated ETV1 and produced increased cell proliferation, hyperplasia, and early prostate intraepithelial neoplasia. Combined loss of COP1 and PTEN enhanced the invasiveness of mouse prostate adenocarcinomas. Finally, rare human prostate cancer samples showed hemizygous loss of the COP1 gene, loss of COP1 protein, and elevated ETV1 protein while lacking a translocation event. These findings identify COP1 as a tumour suppressor whose downregulation promotes prostatic epithelial cell proliferation and tumorigenesis.
Nature 06/2011; 474(7351):403-6. · 36.28 Impact Factor
-
Julie A Di Paolo,
Tao Huang,
Mercedesz Balazs,
James Barbosa,
Kai H Barck,
Brandon J Bravo,
Richard A D Carano,
James Darrow,
Douglas R Davies,
Laura E DeForge, [......],
Scott A Mitchell,
Hong Rong,
Bart L Staker,
J Andrew Whitney,
Sherry Yeh,
Wendy B Young,
Christine Yu,
Juan Zhang,
Karin Reif,
Kevin S Currie
[show abstract]
[hide abstract]
ABSTRACT: Bruton's tyrosine kinase (Btk) is a therapeutic target for rheumatoid arthritis, but the cellular and molecular mechanisms by which Btk mediates inflammation are poorly understood. Here we describe the discovery of CGI1746, a small-molecule Btk inhibitor chemotype with a new binding mode that stabilizes an inactive nonphosphorylated enzyme conformation. CGI1746 has exquisite selectivity for Btk and inhibits both auto- and transphosphorylation steps necessary for enzyme activation. Using CGI1746, we demonstrate that Btk regulates inflammatory arthritis by two distinct mechanisms. CGI1746 blocks B cell receptor-dependent B cell proliferation and in prophylactic regimens reduces autoantibody levels in collagen-induced arthritis. In macrophages, Btk inhibition abolishes FcγRIII-induced TNFα, IL-1β and IL-6 production. Accordingly, in myeloid- and FcγR-dependent autoantibody-induced arthritis, CGI1746 decreases cytokine levels within joints and ameliorates disease. These results provide new understanding of the function of Btk in both B cell- or myeloid cell-driven disease processes and provide a compelling rationale for targeting Btk in rheumatoid arthritis.
Nature Chemical Biology 01/2011; 7(1):41-50. · 14.69 Impact Factor
-
Martin Schwickart,
Xiaodong Huang,
Jennie R Lill,
Jinfeng Liu, Ronald Ferrando,
Dorothy M French,
Heather Maecker,
Karen O'Rourke,
Fernando Bazan,
Jeffrey Eastham-Anderson,
Peng Yue,
David Dornan,
David C S Huang,
Vishva M Dixit
[show abstract]
[hide abstract]
ABSTRACT: MCL1 is essential for the survival of stem and progenitor cells of multiple lineages, and is unique among pro-survival BCL2 family members in that it is rapidly turned over through the action of ubiquitin ligases. B- and mantle-cell lymphomas, chronic myeloid leukaemia, and multiple myeloma, however, express abnormally high levels of MCL1, contributing to chemoresistance and disease relapse. The mechanism of MCL1 overexpression in cancer is not well understood. Here we show that the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival. USP9X binds MCL1 and removes the Lys 48-linked polyubiquitin chains that normally mark MCL1 for proteasomal degradation. Increased USP9X expression correlates with increased MCL1 protein in human follicular lymphomas and diffuse large B-cell lymphomas. Moreover, patients with multiple myeloma overexpressing USP9X have a poor prognosis. Knockdown of USP9X increases MCL1 polyubiquitination, which enhances MCL1 turnover and cell killing by the BH3 mimetic ABT-737. These results identify USP9X as a prognostic and therapeutic target, and they show that deubiquitinases may stabilize labile oncoproteins in human malignancies.
Nature 12/2009; 463(7277):103-7. · 36.28 Impact Factor
-
Martin Schwickart,
XiaoDong Huang,
Jennie R. Lill,
Jinfeng Liu, Ronald Ferrando,
Dorothy M. French,
Heather Maecker,
Karen O’Rourke,
Fernando Bazan,
Jeffrey Eastham-Anderson,
Peng Yue,
David Dornan,
David C. S. Huang,
Vishva M. Dixit
Nature 12/2009; 463(7277):103-107. · 36.28 Impact Factor
