SIAH, the human homologue of the Drosophila seven in absentia (sina) gene, is a tumor suppressor protein that is expressed in intestinal epithelium and activated during apoptosis. Human SIAH proteins are produced as two distinct gene products, SIAH-1, and a slightly larger protein SIAH-2, which share a highly conserved C-terminal sequence and differ in their N-terminal regions. SIAH-1 is a 32 kDa protein that contains an N-terminal RING-finger domain, which is required for proteolysis, and a cystein-rich C-terminal domain, which regulates oligomerization and SIAH binding to target proteins. As a tumor suppressor, SIAH-1 binds DCC (deleted in colorectal cancer) and regulates DCC degradation via the ubiquitin-proteasome pathway. SIAH-1 also binds a Bcl-2 related protein, Bag-1, thereby inhibiting cell growth. The majority of SIAH-1 is localized to the nucleus, however a small percentage is detected in the cytoplasm. This nuclear localization suggests that SIAH proteins may interact with other nuclear matrix proteins and DNA.