- c-Jun is a transcription factor that belongs to the Jun family of proteins, which includes c-Jun, JunB, and JunD.
- It was first identified as the cellular homolog of the viral oncoprotein v-Jun from avian sarcoma virus.
- As a major component of the Activator Protein-1 (AP-1) transcription factor complex, c-Jun regulates a wide variety of genes that govern cell proliferation, differentiation, apoptosis, and responses to environmental stress. Because of its broad regulatory influence, c-Jun plays fundamental roles in both normal physiology and disease.
- Structurally, c-Jun is a basic leucine zipper (bZIP) protein that dimerizes either with itself or with other AP-1 family proteins such as c-Fos, FosB, Fra-1, and Fra-2. This dimerization is critical for DNA binding and transcriptional regulation. The activity of c-Jun is tightly controlled by post-translational modifications, most notably phosphorylation. The c-Jun N-terminal kinases (JNKs) phosphorylate c-Jun at serine residues 63 and 73, an event that greatly enhances its transcriptional activity. Other kinases, including ERK and GSK3, also influence c-Jun function by either promoting or inhibiting its activity depending on the cellular context. Through these modifications, c-Jun acts as a sensitive integrator of intracellular signaling pathways.
- In physiological terms, c-Jun is deeply involved in regulating cell fate. It supports cell proliferation by activating genes such as cyclin D1, while also providing survival signals that counteract apoptosis. In some conditions, however, c-Jun can promote programmed cell death, demonstrating that its role is highly context-dependent. During embryonic development, c-Jun is indispensable; mice lacking c-Jun die around embryonic day 12.5 due to severe defects in liver and heart formation. In adult tissues, c-Jun is rapidly induced by stimuli such as ultraviolet radiation, cytokines, and growth factors, allowing cells to adapt by altering their transcriptional programs.
- The dysregulation of c-Jun is strongly linked to human disease, particularly cancer. Elevated expression or persistent activation of c-Jun has been observed in many tumors, where it drives uncontrolled proliferation, resistance to apoptosis, and enhanced invasiveness. One mechanism underlying tumor invasion is the c-Jun-mediated induction of matrix metalloproteinases, which degrade extracellular matrix and facilitate metastasis. Moreover, c-Jun can suppress tumor suppressor pathways, thereby amplifying its oncogenic potential. Beyond cancer, aberrant c-Jun activity has also been implicated in neurodegeneration, inflammatory disorders, and pathological responses to tissue injury.
- An important aspect of c-Jun regulation involves its turnover by the ubiquitin–proteasome system. The E3 ubiquitin ligase COP1 (also known as RFWD2) has been identified as a key regulator that targets c-Jun for ubiquitination and subsequent degradation. When COP1 is localized to the nucleoplasm, it can directly interact with c-Jun, leading to its downregulation. In conditions where COP1 function is lost or impaired, c-Jun accumulates, which in turn enhances AP-1 activity and promotes tumor progression. This regulatory axis highlights the delicate balance required to maintain appropriate c-Jun levels, and it underscores why c-Jun is considered a pivotal transcription factor at the crossroads of development, stress response, and oncogenesis.
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