The Tumor-Suppressor BAP1 Promotes Expression of Differentiation Genes in Ectodermal Derivatives

MARY LOU KING; JEFFIM KUZNETSOV; TRISTÁN AGÜERO; WILLIAM HARBOUR

Creta

Conferencia; 16th International Xenopus Conference; 2016

Loss-of-functionmutations in the BAP1 tumor suppressor gene are strongly associated with humancancers, including melanoma and mesothelioma. In mice, Bap1 mutant embryos diein utero preventing a molecular analysis of its role in development. BAP1 is amono deubiquitinase and well conserved between humans and Xenopus.  A single substitution in the deubiquitinasecatalytic domain results in a Bap1 dominant negative form functioning withinthe nucleus. Depletion of Bap1 protein leads to defects in gastrulation andloss of differentiation of ectodermal derivatives. Differentiation markers aredown-regulated in the absence of Bap1 function, resembling key results found inmelanoma cell cultures. Alternations in gene expression were rescued byinjection of human or Xenopus Bap1 RNA. We present evidence that BAP1 functionsat the chromatin level interacting with the polycomb complex.  We are developing a high throughput screen toidentify compounds able to revert the striking phenotypes of BAP1 mutants inXenopus.