Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Cell Rep. 2023 Mar 28;42(3):112252. doi: 10.1016/j.celrep.2023.112252. Epub 2023 Mar 14.
Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of heterogeneity remain unclear. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAF expression. We found that a narrow expression range of BRAF generated a wide range of activities of its downstream effector ERK. In population-level and single-cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the ERK-proliferation response. Altogether, our studies map the input-output relationships between ERK activity and proliferation, elucidating how heterogeneity can be generated during oncogene induction.
癌基因诱导的衰老（Oncogene-induced senescence）是一种异常癌基因表达导致非转化细胞进入非增殖状态的现象。发生癌基因诱导的细胞表现出表型异质性，一些细胞衰老，而另一些细胞仍保持增殖状态。异质性的原因尚不清楚。我们研究了人上皮细胞对致癌 BRAF 表达反应的异质性来源。我们发现，BRAF 的表达范围很窄，但其下游效应物 ERK 的活性范围却很宽。在群体水平和单细胞测定中，ERK 活性与增殖呈非单调关系，中等 ERK 活性导致最大增殖。我们对一段时间内 ERK 活性范围内的基因表达进行了分析，并对四种不同的 ERK 反应类型进行了特征描述，我们提出这些类型共同作用产生 ERK-增殖反应。总之，我们的研究绘制了 ERK 活性与增殖之间的输入-输出关系，阐明了在癌基因诱导过程中如何产生异质性。
