Gupta Shantanu, Silveira Daner A, Mombach José Carlos M, Hashimoto Ronaldo F
Instituto de Matemática e Estatística, Departamento de Ciência da Computação, Universidade de São Paulo, Rua do Matão 1010, São Paulo 05508-090, SP, Brazil.
Children's Cancer Institute, Porto Alegre 90620-110, RS, Brazil.
Proteomes. 2025 Jan 20;13(1):6. doi: 10.3390/proteomes13010006.
The tumor suppressor p53, in its wild-type form, plays a central role in cellular homeostasis by regulating senescence, apoptosis, and autophagy within the DNA damage response (DDR). Recent findings suggest that wild-type p53 also governs ferroptosis, an iron-dependent cell death process driven by lipid peroxidation. Post-translational modifications of p53 generate proteoforms that significantly enhance its functional diversity in regulating these mechanisms. A key target in this process is the cystine/glutamate transporter (xCT), which is essential for redox balance and ferroptosis resistance. Additionally, p53-induced miR-34c-5p suppresses cancer cell proliferation and drug resistance by modulating Myc, an oncogene further influenced by non-coding RNAs like circular RNA NOTCH1 (CricNOTCH1) and long non-coding RNA MALAT1. However, the exact role of these molecules in ferroptosis remains unclear. To address this, we introduce the first dynamic Boolean model that delineates the influence of these ncRNAs and p53 on ferroptosis, apoptosis, and senescence within the DDR context. Validated through gain- and loss-of-function perturbations, our model closely aligns with experimental observations in cancers such as oral squamous cell carcinoma, nasopharyngeal carcinoma, and osteosarcoma. The model identifies crucial positive feedback loops (CricNOTCH1/miR-34c/Myc, MALAT1/miR-34c/Myc, and Myc/xCT) and highlights the therapeutic potential of using p53 proteoforms and ncRNAs to combat drug resistance and induce cancer cell death.
肿瘤抑制因子p53的野生型形式通过在DNA损伤反应（DDR）中调节衰老、凋亡和自噬，在细胞稳态中发挥核心作用。最近的研究结果表明，野生型p53还调控铁死亡，这是一种由脂质过氧化驱动的铁依赖性细胞死亡过程。p53的翻译后修饰产生的蛋白变体在调节这些机制方面显著增强了其功能多样性。这一过程中的一个关键靶点是胱氨酸/谷氨酸转运体（xCT），它对氧化还原平衡和铁死亡抗性至关重要。此外，p53诱导的miR-34c-5p通过调节Myc抑制癌细胞增殖和耐药性，Myc是一种癌基因，还受到环状RNA NOTCH1（CricNOTCH1）和长链非编码RNA MALAT1等非编码RNA的进一步影响。然而，这些分子在铁死亡中的确切作用仍不清楚。为了解决这个问题，我们引入了第一个动态布尔模型，该模型描述了这些非编码RNA和p53在DDR背景下对铁死亡、凋亡和衰老的影响。通过功能获得和功能丧失扰动验证，我们的模型与口腔鳞状细胞癌、鼻咽癌和骨肉瘤等癌症的实验观察结果密切吻合。该模型确定了关键的正反馈回路（CricNOTCH1/miR-34c/Myc、MALAT1/miR-34c/Myc和Myc/xCT），并突出了使用p53蛋白变体和非编码RNA对抗耐药性和诱导癌细胞死亡的治疗潜力。
