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BAP1 binds VHL. 16 / 16
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"Additionally, in vitro binding assays demonstrated that purified glutathione S -transferase (GST)–BAP1, but not GST alone, could directly interact with recombinant His-VHL, confirming a direct interaction between BAP1 and pVHL ( xref )."
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"Given the direct interaction between BAP1 and pVHL, thus, we further investigated whether BAP1 could suppress CRC progression by regulating pVHL stability and function."
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"While a single knockout of Vhl and Pbrm1 failed to develop kidney cancer in mice, both Bap1-Vhl and Bap1-Pbrm1 double-knockout mice developed ccRCC [ xref , xref , xref ]."
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"We also confirmed that the BAP1-pVHL axis is applicable in pancreatic and ovarian cancer (fig."
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"First, BAP1 directly interacts with pVHL in cells and in vitro ( xref )."
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"In keeping with their previous work demonstrating that BAP1 loss results in mTOR activation, the authors found that Vhl-Bap1 –deficient tumors showed strong phospho-S6 (pS6) expression."
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"In addition, we examined the potential functions of the BAP1-pVHL axis in other tumor types."
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"The faithful Vhl-Bap1 and Vhl-Pbrm1 GEM models developed by Gu and colleagues add to the recent salvo of GEM models of ccRCC based upon concurrent deletion of Vhl, p53 , and Rb1 by Frew and colleagues or the inactivation of Vhl and Cdkn2a with concurrent activation of MYC by our group ( xref , xref )."
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"The endogenous interaction between BAP1 and pVHL was further validated through co-immunoprecipitation assays in HCT116 cells ( xref )."
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"Mice deficient for either VHL or VHL together with one allele of BAP1 developed multiple lesions spanning from benign cysts to cystic and solid ccRCC XREF_BIBR suggesting a tumor suppressive cooperation between BAP1 and pVHL."
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"Given the established direct interaction between BAP1 and pVHL, we next investigated whether pVHL itself undergoes UFMylation."
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"Conversely, loss of UFMylation, either through UFL1 depletion or by reconstitution with the UFMylation-defective BAP1 mutant 4KR, markedly impairs the BAP1-pVHL interaction, leading to reduced stabilization of pVHL and a consequent loss of tumor-suppressive properties."
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"The association between VHL, PBRM1, BAP1, SETD2 AND KDM5C mutation status and overall survival was evaluated in 167 patients with metastatic ccRCC who underwent genomic sequencing of their primary tumor."
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"Despite the critical role of UFMylation in stabilizing the BAP1-pVHL axis, translating this mechanism into therapeutic strategies faces challenges due to the pleiotropic nature of UFM1, which modifies multiple cellular proteins beyond BAP1."
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"The instability of pVHL in UFL1-depleted cells may result from the impaired interaction between BAP1 and pVHL, while BAP1 interaction with other substrates, such as LKB1 and SLC7A11, remains unaffected (fig."
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"All three genes are located on chromosome 3p, as is VHL and as noted earlier, inactivation of both VHL and Bap1 in mice leads to both cystic and neoplastic lesions [86]; clearly, definition of the functional interactions between VHL, BAP1, PBRM1, and SET is a topic of urgent interest."
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