Stimulation of de Novo Pyrimidine Synthesis by Growth Signaling Through mTOR and

Cellular growth signals stimulate anabolic processes. The mechanistic target of rapamycin complex 1 (mTORC1) is a proteinkinase that senses growth signals to regulate anabolic growth and proliferation. Activation of mTORC1 led to the acute stimulationof metabolic flux through the de novo pyrimidine synthesis pathway. mTORC1 signaling posttranslationally regulated this metabolicpathway via its downstream target ribosomal protein S6 kinase 1 (S6K1), which directly phosphorylates S1859 on CAD (carbamoyl-phosphatesynthetase 2, aspartate transcarbamoylase, dihydroorotase), the enzyme that catalyzes the first three steps of de novo pyrimidinesynthesis. Growth signaling through mTORC1 thus stimulates the production of new nucleotides to accommodate an increase inRNA and DNA synthesis needed for ribosome biogenesis and anabolic growth.