c-Jun regulates cell cycle progression and apoptosis by distinct mechanisms

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Abstract
C‐Jun is a component of the transcription factor AP‐1, which is activated by a wide variety of extracellular stimuli. The regulation of c‐Jun is complex and involves both increases in the levels of c‐Jun protein as well as phosphorylation of specific serines (63 and 73) by Jun N‐terminal kinase (JNK). We have used fibroblasts derived from c‐Jun null embryos to define the role of c‐Jun in two separate processes: cell growth and apoptosis. We show that in fibroblasts, c‐Jun is required for progression through the G1 phase of the cell cycle; c‐Jun‐mediated G1 progression occurs by a mechanism that involves direct transcriptional control of the cyclin D1 gene, establishing a molecular link between growth factor signaling and cell cycle regulators. In addition, c‐Jun protects cells from UV‐induced cell death and cooperates with NF‐κB to prevent apoptosis induced by tumor necrosis factor alpha (TNFα). c‐Jun mediated G1 progression is independent of phosphorylation of serines 63/73; however, protection from apoptosis in response to UV, a potent inducer of JNK/SAP kinase activity, requires serines 63/73. The results reveal critical roles for c‐Jun in two different cellular processes and show that different extracellular stimuli can target c‐Jun by distinct biochemical mechanisms.