Department of Internal Medicine, Virginia Commonwealth University (VCU), Richmond, VA, USA; VCU Massey Cancer Center, VCU, Richmond, VA, USA.
Kronos Bio, Inc., Cambridge, MA, USA.
Cell Rep. 2019 Mar 19;26(12):3323-3335.e4. doi: 10.1016/j.celrep.2019.02.076.
The control of p53 protein stability is critical to its tumor suppressor functions. The CREB binding protein (CBP) transcriptional co-activator co-operates with MDM2 to maintain normally low physiological p53 levels in cells via exclusively cytoplasmic E4 polyubiquitination activity. Using mass spectrometry to identify nuclear and cytoplasmic CBP-interacting proteins that regulate compartmentalized CBP E4 activity, we identified deleted in breast cancer 1 (DBC1) as a stoichiometric CBP-interacting protein that negatively regulates CBP-dependent p53 polyubiquitination, stabilizes p53, and augments p53-dependent apoptosis. TCGA analysis demonstrated that solid tumors often retain wild-type p53 alleles in conjunction with DBC1 loss, supporting the hypothesis that DBC1 is selected for disruption during carcinogenesis as a surrogate for p53 functional loss. Because DBC1 maintains p53 stability in the nucleus, where p53 exerts its tumor-suppressive transcriptional function, replacement of DBC1 functionality in DBC1-deleted tumors might enhance p53 function and chemosensitivity for therapeutic benefit.
p53 蛋白稳定性的控制对其肿瘤抑制功能至关重要。CREB 结合蛋白（CBP）转录共激活因子通过专有的细胞质 E4 多泛素化活性与 MDM2 合作，维持细胞中正常的低生理 p53 水平。我们使用质谱法鉴定了核和细胞质 CBP 相互作用蛋白，这些蛋白可调节区室化 CBP E4 活性，发现乳腺癌缺失基因 1（DBC1）是 CBP 的一种化学计量相互作用蛋白，可负调控 CBP 依赖性 p53 多泛素化，稳定 p53，并增强 p53 依赖性细胞凋亡。TCGA 分析表明，固体肿瘤通常与 DBC1 缺失一起保留野生型 p53 等位基因，支持这样一种假说，即在癌变过程中选择破坏 DBC1 作为 p53 功能丧失的替代物。由于 DBC1 在细胞核中维持 p53 的稳定性，而 p53 在细胞核中发挥其肿瘤抑制转录功能，因此在 DBC1 缺失的肿瘤中替换 DBC1 的功能可能会增强 p53 的功能和化学敏感性，从而带来治疗益处。
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