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Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis
1Cancer Research Institute, University of California San Francisco, San Francisco, California 94143, USA.
Abstract:
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.
Insights
The CC3 gene suppresses small cell lung cancer metastasis by inducing cell death. An alternative form, TC3, has opposite anti-apoptotic effects and is rapidly degraded by proteasomes.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The CC3 gene acts as a metastasis suppressor in small cell lung carcinoma (SCLC).
- Tumor cell apoptotic resistance is a key factor in metastasis.
- CC3's mechanism involves impairing this resistance.
Purpose of the Study:
- To investigate an alternatively spliced RNA of CC3, named TC3.
- To characterize the functional and regulatory properties of TC3.
- To understand the opposing roles of CC3 and TC3 in apoptosis.
Main Methods:
- Analysis of alternatively spliced RNA variants (CC3 and TC3).
- Overexpression studies in rodent fibroblasts to assess cell death and survival.
- Investigation of protein degradation pathways, including proteasome interaction.
- Examination of protein domains responsible for apoptotic and anti-apoptotic activities.
Main Results:
- TC3 encodes an unstable protein with anti-apoptotic activity, contrasting CC3's pro-apoptotic function.
- TC3 protects cells from CC3-induced death and other death stimuli.
- The unique carboxyl terminus of TC3 confers anti-apoptotic function and targets it for rapid proteasomal degradation.
- CC3's death-inducing activity involves mitochondrial membrane potential disruption.
Conclusions:
- CC3 and TC3 represent a novel dual regulator of cell death with opposing functions.
- TC3's instability and anti-apoptotic role are mediated by its unique carboxyl terminus and proteasomal degradation.
- Understanding CC3 and TC3 provides new insights into apoptosis regulation and potential therapeutic strategies for SCLC.