Multiple MAPK Cascades Regulate the Transcription of <i>IME1</i>, the Master Transcriptional Activator of Meiosis in <i>Saccharomyces cerevisiae</i>

The choice between alternative developmental pathways is primarily controlled at the level of transcription. Induction of meiosis in budding yeasts in response to nutrient levels provides a system to investigate the molecular basis of cellular decision-making. In Saccharomyces cerevisiae, entry into meiosis depends on multiple signals converging upon IME1, the master transcriptional activator of meiosis. Here we studied the regulation of the cis-acting regulatory element Upstream Activation Signal (UAS)ru, which resides within the IME1 promoter. Guided by our previous data acquired using a powerful high-throughput screening system, here we provide evidence that UASru is regulated by multiple stimuli that trigger distinct signal transduction pathways as follows: (i) The glucose signal inhibited UASru activity through the cyclic AMP (cAMP/protein kinase A (PKA) pathway, targeting the transcription factors (TFs), Com2 and Sko1; (ii) high osmolarity activated UASru through the Hog1/mitogen-activated protein kinase (MAPK) pathway and its corresponding TF Sko1; (iii) elevated temperature increased the activity of UASru through the cell wall integrity pathway and the TFs Swi4/Mpk1 and Swi4/Mlp1; (iv) the nitrogen source repressed UASru activity through Sum1; and (v) the absence of a nitrogen source was detected and transmitted to UASru by the Kss1 and Fus3 MAPK pathways through their respective downstream TFs, Ste12/Tec1 and Ste12/Ste12 as well as by their regulators Dig1/2. These signaling events were specific to UASru; they did not affect the mating and filamentation response elements that are regulated by MAPK pathways. The complex regulation of UASru through all the known vegetative MAPK pathways is unique to S. cerevisiae and is specific for IME1, likely because it is the master regulator of gametogenesis.细胞发育通路的选择主要在转录水平受到调控。酿酒酵母（Saccharomyces cerevisiae）响应营养水平诱导减数分裂的过程，为研究细胞决策的分子基础提供了优质的研究体系。在酿酒酵母中，进入减数分裂依赖于汇聚至IME1的多种信号——IME1是减数分裂的核心转录激活因子。本研究聚焦于位于IME1启动子内的顺式作用调控元件上游激活信号（Upstream Activation Signal, UAS）ru的调控机制。基于我们此前利用高效高通量筛选系统获得的研究数据，本研究证实UASru受到多种触发不同信号转导通路的刺激因子调控，具体如下： (i) 葡萄糖信号通过环腺苷酸（cyclic AMP, cAMP）/蛋白激酶A（protein kinase A, PKA）通路，靶向转录因子（transcription factors, TFs）Com2和Sko1，抑制UASru的活性； (ii) 高渗透压通过Hog1/丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）通路及其对应转录因子Sko1激活UASru； (iii) 温度升高通过细胞壁完整性通路及转录因子Swi4/Mpk1、Swi4/Mlp1增强UASru活性； (iv) 氮源通过Sum1抑制UASru的活性； (v) 氮源缺失可通过Kss1和Fus3丝裂原活化蛋白激酶通路，经由其下游转录因子Ste12/Tec1、Ste12/Ste12及其调控因子Dig1/2，感知并传递信号至UASru。 上述信号事件对UASru具有特异性，不会影响受MAPK通路调控的交配及丝状生长应答元件。UASru通过所有已知的营养生长MAPK通路受到复杂调控，这一调控模式为酿酒酵母所特有，且仅针对IME1，这很可能是因为IME1作为配子发生的核心调控因子所致。