Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis

The human gene CC3 is a metastasis suppressor for small cell lung carcinoma (SCLC) in vivo. The ability of CC3 to impair the apoptotic resistance of tumor cells is likely to contribute to metastasis suppression. We describe here an alternatively spliced RNA of CC3, designated TC3, that encodes an unstable protein with antiapoptotic activity. TC3 and CC3 proteins share amino-terminal sequences, but TC3 has a unique short hydrophobic carboxyl terminus. Overexpression of CC3 results in massive death of rodent fibroblasts, but TC3 protects cells from CC3-induced death and from other death stimuli such as treatment with tumor necrosis factor or overexpression of Bax protein. The death-inducing activity of CC3 resides within its amino-terminal domain, which is conserved in TC3. The carboxyl terminus of TC3 is responsible for the antiapoptotic function of TC3; mutations in this domain abolish the ability of TC3 to protect cells from apoptosis. TC3 protein is short-lived due to its rapid degradation by proteasome, and it forms complexes with a regulatory subunit of proteasome known as s5alpha. The signal for the rapid degradation of TC3 resides within its carboxyl terminus, which is capable of conferring instability on a heterologous protein. The proapoptotic activity of CC3 in SCLC cells is induced by a wide variety of signals and involves disruption of the mitochondrial membrane potential (Deltapsim). The CC3 protein has sequence similarity to bacterial short-chain dehydrogenases/reductases and might represent a phylogenetically old effector of cell death similar to the recently identified apoptosis-inducing factor. CC3 and TC3 have opposing functions in apoptosis and represent a novel dual regulator of cell death.