尽管在92%的TP53突变癌症中发生了突变,p53同工型的突变如何影响它们的活性仍然是未知的.因此,探索突变对p53同工型活性的影响是至关重要的,尽管在p53领域尚未探索的领域。在这篇文章中,我们首次报道了突变的Δ133p53α特异性途径,该途径增加了IL4I1和IDO1的表达并激活了AHR,促进肿瘤的机制。因此,而WTΔ133p53α减少细胞凋亡以促进DNA修复,突变体R273H也减少细胞凋亡,但不能保持基因组的稳定性,增加突变积累和肿瘤向更具侵袭性表型的风险。此外,使用2D和3D球体培养,我们显示WTΔ133p53α减少细胞增殖,EMT,和入侵,而突变体Δ133p53αR273H增强了所有三个过程,证实了其致癌潜力,并强烈暗示了类似的体内活性。重要的是,对细胞生长和侵袭的影响与突变体全长p53α无关,表明这些活性由突变体Δ133p53αR273H积极携带。此外,WT和突变型Δ133p53α均以衰老诱导剂依赖性方式(替莫唑胺或辐射)降低细胞衰老,因为它们调节不同的衰老相关靶基因。因此,WTΔ133p53α挽救了替莫唑胺诱导的衰老,但不是辐射诱导的衰老,而突变体Δ133p53αR273H挽救了辐射诱导的衰老,但不是替莫唑胺诱导的衰老。最后,我们确定IL4I1,IDO1和AHR在GBM中显著高于低级别胶质瘤.重要的是,LGG和IL4I1在GBM中的所有三个基因的高表达与较差的患者生存率显着相关,证实该途径在胶质母细胞瘤中的临床相关性。这些数据表明,与WTΔ133p53α相比,R273H突变将其活性重新定向为致癌作用,并激活致癌IL4I1/IDO1/AHR途径,通过结合特异性调节Δ133p53α表达的药物和IDO1/Il4I1/AHR抑制剂,成为GBM中潜在的预后标志物和治疗靶标。
Despite being mutated in 92% of TP53 mutant cancers, how mutations on p53 isoforms affect their activities remain largely unknown. Therefore, exploring the effect of mutations on p53 isoforms activities is a critical, albeit unexplored area in the p53 field. In this article, we report for the first time a mutant Δ133p53α-specific pathway which increases IL4I1 and IDO1 expression and activates AHR, a tumor-promoting mechanism. Accordingly, while WT Δ133p53α reduces apoptosis to promote DNA repair, mutant R273H also reduces apoptosis but fails to maintain genomic stability, increasing the risks of accumulation of mutations and tumor\'s deriving towards a more aggressive phenotype. Furthermore, using 2D and 3D spheroids culture, we show that WT Δ133p53α reduces cell proliferation, EMT, and invasion, while the mutant Δ133p53α R273H enhances all three processes, confirming its oncogenic potential and strongly suggesting a similar in vivo activity. Importantly, the effects on cell growth and invasion are independent of mutant full-length p53α, indicating that these activities are actively carried by mutant Δ133p53α R273H. Furthermore, both WT and mutant Δ133p53α reduce cellular senescence in a senescence inducer-dependent manner (temozolomide or radiation) because they regulate different senescence-associated target genes. Hence, WT Δ133p53α rescues temozolomide-induced but not radiation-induced senescence, while mutant Δ133p53α R273H rescues radiation-induced but not temozolomide-induced senescence. Lastly, we determined that IL4I1, IDO1, and AHR are significantly higher in GBMs compared to low-grade gliomas. Importantly, high expression of all three genes in LGG and IL4I1 in GBM is significantly associated with poorer patients\' survival, confirming the clinical relevance of this pathway in glioblastomas. These data show that, compared to WT Δ133p53α, R273H mutation reorientates its activities toward carcinogenesis and activates the oncogenic IL4I1/IDO1/AHR pathway, a potential prognostic marker and therapeutic target in GBM by combining drugs specifically modulating Δ133p53α expression and IDO1/Il4I1/AHR inhibitors.