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缺失选择性剪接 p53 异构体的突变型小鼠揭示了在 Myc 驱动的 B 细胞淋巴瘤中作为一个男性特异性预后因素的。

Mutant mice lacking alternatively spliced p53 isoforms unveil as a male-specific prognostic factor in Myc-driven B-cell lymphomas.

机构信息

Genetics of Tumor Suppression, Institut Curie, Paris, France.

CNRS UMR3244, Paris, France.

出版信息

Elife. 2024 Sep 19;13:RP92774. doi: 10.7554/eLife.92774.

DOI:10.7554/eLife.92774
PMID:39298333
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11412721/
Abstract

The gene encodes several isoforms of elusive biological significance. Here, we show that mice lacking the alternatively spliced (AS) exon, thereby expressing the canonical p53 protein but not isoforms with the AS C-terminus, have unexpectedly lost a male-specific protection against Myc-induced B-cell lymphomas. Lymphomagenesis was delayed in males compared to males, but also compared to and females. Pre-tumoral splenic cells from males exhibited a higher expression of encoding an atypical chemokine receptor with tumor suppressive effects. We identified as a p53 target gene whose p53-mediated transactivation is inhibited by estrogens, and as a male-specific factor of good prognosis relevant for murine -induced and human Burkitt lymphomas. Furthermore, the knockout of increased the chemokine-guided migration of Burkitt lymphoma cells. These data demonstrate the functional relevance of alternatively spliced p53 isoforms and reveal sex disparities in Myc-driven lymphomagenesis.

摘要

该基因编码几种具有难以捉摸的生物学意义的异构体。在这里，我们表明，缺乏可变剪接（AS）外显子的小鼠，从而表达典型的 p53 蛋白，但不表达具有 AS C 末端的异构体，出人意料地失去了对 Myc 诱导的 B 细胞淋巴瘤的雄性特异性保护。与雄性相比，淋巴瘤的发生被延迟，但与雌性相比也是如此。来自雄性的前肿瘤性脾细胞表现出更高表达编码具有肿瘤抑制作用的非典型趋化因子受体的 。我们将其鉴定为 p53 靶基因，其 p53 介导的反式激活被雌激素抑制，并且是与雄性相关的、与小鼠诱导的和人类伯基特淋巴瘤相关的良好预后的特异性因素。此外， 基因的敲除增加了伯基特淋巴瘤细胞的趋化因子导向迁移。这些数据表明了可变剪接的 p53 异构体的功能相关性，并揭示了 Myc 驱动的淋巴瘤发生中的性别差异。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3156/11412721/39f3adc12533/elife-92774-fig4-figsupp4.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3156/11412721/224247b21644/elife-92774-fig4.jpg
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