DEPDC1/LET-99 participates in an evolutionarily conserved pathway for anti-tubulin drug-induced apoptosis

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• Microtubule-targeting chemotherapeutics are crucial in cancer treatment, inducing apoptosis via MCL1 degradation.
• The precise signaling pathways connecting microtubule disruption to MCL1 degradation are not fully understood.

Purpose of the Study:

• To identify novel genes involved in chemotherapy-induced apoptosis using an in vivo screening approach.
• To elucidate the signaling cascade regulating MCL1 degradation in response to anti-tubulin drugs.

Main Methods:

• An RNA interference (RNAi)-based in vivo screening strategy was employed in Caenorhabditis elegans.
• Functional conservation of identified genes was assessed in human cell lines.

Main Results:

• Three genes essential for vincristine-induced apoptosis were identified in C. elegans.
• The DEP domain protein LET-99 was found to act upstream of GPA-11 and JNK-1 activation.
• The human homologue DEPDC1 was shown to regulate vincristine-induced cell death via JNK-dependent MCL1 degradation.

Conclusions:

• LET-99 and its human homologue DEPDC1 are evolutionarily conserved mediators of anti-tubulin drug-induced apoptosis.
• DEPDC1 acts upstream of MCL1, suggesting its levels may predict response to microtubule-targeting therapies.