SAG/ROC2 E3 ligase regulates skin carcinogenesis by stage-dependent targeting of c-Jun/AP1 and...

Area of Science:

• Molecular Biology
• Cancer Research
• Cellular Signaling

Background:

• The Sensitive to apoptosis gene (SAG) is a component of the SCF E3 ubiquitin ligase complex, regulating protein degradation.
• Ubiquitination and protein degradation are critical cellular processes involved in various biological functions, including cell proliferation and apoptosis.

Purpose of the Study:

• To investigate the role of SAG in epidermal carcinogenesis.
• To elucidate the mechanisms by which SAG influences tumor initiation, progression, and apoptosis.

Main Methods:

• Expression of SAG in mouse epidermis using the K14 promoter.
• Inhibition of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB) signaling pathways.
• Assessment of epidermal proliferation and apoptosis in response to chemical carcinogens (7,12-dimethylbenz(a)-anthracene/12-O-tetradecanoylphorbol-13-acetate).
• Analysis of tumor formation, latency, and frequency in transgenic mouse models.

Main Results:

• SAG expression inhibited TPA-induced c-Jun levels and AP-1 activity, suppressing early-stage epidermal proliferation during carcinogenesis.
• SAG expression significantly inhibited tumor formation, prolonging latency and reducing frequency.
• Conversely, SAG expression enhanced later-stage tumor growth by reducing apoptosis, partly due to NF-kappaB activation.
• SAG promoted inhibitor of kappaBalpha degradation, leading to NF-kappaB activation and subsequent inhibition of apoptosis.

Conclusions:

• SAG exhibits dual roles in carcinogenesis: early-stage suppression via AP-1 inhibition and later-stage promotion through NF-kappaB activation and reduced apoptosis.
• The function of SAG is dependent on the availability of F-box proteins, influencing its substrate specificity.
• Targeting SAG or its downstream pathways may offer therapeutic strategies for cancer prevention and treatment.