Bhavani Gottumukkala Sai, Palanisamy Anbumathi
Department of Biotechnology, NIT Warangal, India.
Biomed Phys Eng Express. 2022 Jun 24;8(4). doi: 10.1088/2057-1976/ac7896.
Epithelial to Mesenchymal Transition (EMT) plays an important role in tissue regeneration, embryonic development, and cancer metastasis. Several signaling pathways are known to regulate EMT, among which the modulation of TGF(Transforming Growth Factor-) induced EMT is crucial in several cancer types. Several mathematical models were built to explore the role of core regulatory circuit of ZEB/miR-200, SNAIL/miR-34 double negative feedback loops in modulating TGFinduced EMT. Different emergent behavior including tristability, irreversible switching, existence of hybrid EMT states were inferred though these models. Some studies have explored the role of TGFreceptor activation, SMADs nucleocytoplasmic shuttling and complex formation. Recent experiments have revealed that MDM2 along with SMAD complex regulates SNAIL expression driven EMT. Encouraged by this, in the present study we developed a mathematical model for p53/MDM2 dependent TGFinduced EMT regulation. Inclusion of p53 brings in an additional mechanistic perspective in exploring the EM transition. The network formulated comprises a C1FFL moderating SNAIL expression involving MDM2 and SMAD complex, which functions as a noise filter and persistent detector. The C1FFL was also observed to operate as a coincidence detector driving the SNAIL dependent downstream signaling into phenotypic switching decision. Systems modelling and analysis of the devised network, displayed interesting dynamic behavior, systems response to various inputs stimulus, providing a better understanding of p53/MDM2 dependent TGF-induced Epithelial to Mesenchymal Transition.
上皮-间质转化（EMT）在组织再生、胚胎发育和癌症转移中起着重要作用。已知有几种信号通路可调节EMT，其中TGF（转化生长因子-）诱导的EMT调节在几种癌症类型中至关重要。构建了几个数学模型来探索ZEB/miR-200、SNAIL/miR-34双负反馈回路的核心调节电路在调节TGF诱导的EMT中的作用。通过这些模型推断出了不同的涌现行为，包括三稳态、不可逆切换、混合EMT状态的存在。一些研究探讨了TGF受体激活、SMADs核质穿梭和复合物形成的作用。最近的实验表明，MDM2与SMAD复合物一起调节SNAIL表达驱动的EMT。受此鼓舞并在本研究中，我们开发了一个关于p53/MDM2依赖的TGF诱导的EMT调节的数学模型。纳入p53为探索EM转化带来了一个额外的机制视角。所构建的网络包括一个调节SNAIL表达的C1FFL，涉及MDM2和SMAD复合物，其起到噪声滤波器和持续检测器的作用。还观察到C1FFL作为一个巧合检测器，驱动依赖SNAIL的下游信号进入表型转换决定。对所设计网络的系统建模和分析显示出有趣的动态行为、系统对各种输入刺激的响应，从而更好地理解了p53/MDM依赖的TGF诱导的上皮-间质转化。
