In an effort to elucidate the signaling pathway for DNA damage induced apoptosis; we identified a HECT domain ubiquitin ligase, Mule, as a key regulator of apoptosis by controlling the polyubiquitination and degradation of anti-apoptotic BCL-2 family protein Mcl-1. Later on, Mule null cells are also found to be resistant to HDAC (histone deacetylase) inhibitors, and we identified HDAC2 as a substrate of Mule and showed that this regulation determines the cellular response to HDACis. Both DNA damaging agents and HDACis are broadly used as first-line anti-cancer drugs. We are continuing to understand the biological functions of Mule in apoptosis and other forms of cell death induced by cancer therapeutic agents.
- Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005, 121(7): 1085-1095.
- Zhang J, Kan S, Huang B, Hao Z, Mak TW, Zhong Q. Mule determines the apoptotic response to HDAC inhibitors by targeted ubiquitination and destruction of HDAC2. Genes Dev 2011, Dec 15;25(24):2610-8.