Recent research have found 55 novel CCCH-type zinc finger genes in human, those genes potentially participate in several cellular processes including proliferation, differentiation, apoptosis, anti-virus, immunity and inflammation. We have found several CCCH-type zinc finger genes were abnormally expressed in human colorectal cancer tissues, such as downregulation of Zc3h12a and upregulation of Zc3hav1L in tumor. Zc3h12a (also named MCPIP1) was identified as a transcription factor in monocyte chemotactic protein-1 (MCP-1)-activated monocytes. It exhibits RNase and deubiquitinase activities, and can inhibit inflammation through decrease of NF-B activity. Our preliminary results found overexpression of wild type Zc3h12a resulted in inhibiting cell proliferation and enhanced the TNF-induced cell apoptosis. However, mutant Zc3h12a (D141N) did not inhibit cell proliferation and enhance TNF-induced cell apoptosis. It has been known that TNFα binds to its receptor and subsequently forms TNFR complex I and TNFR complex II, which are associated with the activation of NF-B and caspase-8, respectively. The formation of TNFR complex might contribute to the activation of caspase-1 or caspase-4, which might be the most upstream events in TNFα-induced caspase cascade. Inflammasomes are intracellular protein complexes induced by inflammatory cytokines, which aims to activate caspase-1 and then in turn to cleave pro-IL-1 into IL-1. The “pyroptosis” is a new term to describe the caspase-1-dependent cell death. Our preliminary results found the caspase-1 inhibitor could reverse the Zc3h12a- and TNFα-induced the activation of caspase cascade and apoptosis. Therefore, we thought the Zc3h12a might involve in the inflammasomes and pyroptosis. Zc3hav1 protein has been known that exhibits anti-virus activity by degradation of viral RNA. Another CCCH-type zinc finger gene Zc3hav1-like gene (Zc3hav1L) is similar to Zc3hav1 gene , but it has been little studied previously. Our preliminary results also found knockdown Zc3hav1L significantly inhibited cell proliferation and migration, however overexpression of Zc3hav1L increases cell proliferation and migration. Based on our recent findings and hypothesis, we would like to fully understand the molecular mechanisms of Zc3h12a and Zc3hav1L on the regulation of cell proliferation, apoptosis, migration/metastasis, inflammation, or pyroptosis, and hope to achieve the following Specific Goals. 1. To investigate the molecular mechanisms about Zc3h12a enhances TNF-induced cell apoptosis: to confirm the effects of Zc3h12a enhances TNF-induced cell apoptosis; to examine whether Zc3h12a affects TNF-induced FADD/caspase-8 death pathway; to examine whether Zc3h12a affects TNF-induced NF-B survival pathway and JNK death pathway. 2. To investigate the role of Zc3h12a on the formation of TNFR complex I, complex II, and inflammasomes and pyroptosis: to examine whether Zc3h12a affects the formation of TNFR complex I and complex II; to examine whether Zc3h12a affects inflammasomes and involves in the pyroptosis. 3. To investigate the role of Zc3h12a and Zc3hav1L on the regulation of cell growth in colorectal cancer cells: to examine whether overexpression of Zc3h12a affects cell proliferation, cell cycle progression and apoptosis in colorectal cancer cells; to examine whether decrease or overexpression of Zc3hav1L affects cell growth, migration/metastasis, and apoptosis in colorectal cancer cells.
|Effective start/end date||8/1/13 → 7/31/14|
- CCCH zinc finger gene