Miller Anna K, Munger Karl, Adler Frederick R
Department of Mathematics, University of Utah, Salt Lake City, UT, USA.
Department of Developmental, Molecular and Chemical Biology, Tufts University, Boston, MA, USA.
Bull Math Biol. 2017 Jul;79(7):1564-1585. doi: 10.1007/s11538-017-0299-9. Epub 2017 Jun 12.
Human papillomaviruses (HPVs) that infect mucosal epithelium can be classified as high risk or low risk based on their propensity to cause lesions that can undergo malignant progression. HPVs produce the E7 protein that binds to cell cycle regulatory proteins including the retinoblastoma tumor suppressor protein (RB) to modulate cell cycle control. Generally, high-risk HPV E7 proteins bind to RB with a higher affinity than low-risk HPV E7s, but both are able to deactivate RB and trigger S phase progression. In uninfected cells, RB inactivation is a tightly controlled process that must coincide with growth factor stimulation to commit cells to division. High-risk HPV E7 proteins short-circuit this control by decreasing growth factor requirement for cell division. We develop a mathematical model to examine the role that RB binding affinity, growth factor concentration, and E7 concentration have on cell cycle progression. Our model predicts that high RB binding affinity and E7 concentration accelerate the [Formula: see text] to S phase transition and weaken the dependence on growth factor. This model thus captures a key step in high-risk HPV oncogenesis.
感染黏膜上皮的人乳头瘤病毒（HPV）可根据其导致病变发生恶性进展的倾向分为高危型或低危型。HPV产生E7蛋白，该蛋白与包括视网膜母细胞瘤肿瘤抑制蛋白（RB）在内的细胞周期调节蛋白结合，以调节细胞周期控制。一般来说，高危型HPV E7蛋白与RB的结合亲和力高于低危型HPV E7蛋白，但两者都能够使RB失活并触发S期进展。在未感染的细胞中，RB失活是一个受到严格控制的过程，必须与生长因子刺激同时发生才能使细胞进入分裂状态。高危型HPV E7蛋白通过降低细胞分裂对生长因子的需求来绕过这种控制。我们建立了一个数学模型来研究RB结合亲和力、生长因子浓度和E7浓度对细胞周期进展的作用。我们的模型预测，高RB结合亲和力和E7浓度会加速G1期到S期的转变，并减弱对生长因子的依赖性。因此，该模型抓住了高危型HPV致癌过程中的一个关键步骤。
