The ectopic expression of the entire SEL1L cDNA significantly reduces the proliferate activity and aggressive behavior of the human breast carcinoma cell line MCF-7. However, the mechanism responsible for this biological effect remains unclear. A study was initiated to define those regions within SEL1L conferring such antiproliferative properties. Here we report that the region between amino acid residues 659-794 contains a functionally relevant domain since a deletion mutant impairs SEL1L's ability to suppress tumor cell growth. This region contains the Hrd3 motif, tetratricopeptide (TPR)-like SEL1 repeat, a transmembrane region, and a proline-rich tail.