Abstract
The human homologue of the Drosophila tumor suppressor lethal (2) tumorous imaginal discs (l(2)tid) gene, hTID1, encodes two proteins derived from alternate mRNA splicing. The splice variants TidL and TidS were previously reported from protein overexpression and dominant-negative mutant protein studies to exhibit opposing biological activities in response to exogenous cytotoxic stimuli. TidL was found to promote apoptosis while TidS suppressed it. To elucidate the physiological function of hTID1, we depleted hTID1 proteins using the technique of RNA interference (RNAi). Here, we show that cells essentially lacking expression of hTID1 proteins are protected from cell death in response to multiple stimuli, including cisplatin, tumor necrosis factor alpha/cycloheximide and mitomycin C. We also generated stable cell populations depleted of hTID1 proteins by RNAi using DNA vectors. In addition to apoptosis resistance, stable hTID1 knockdown cells exhibited an enhanced ability for anchorage-independent growth, as measured by an increase in soft-agar colony formation. These results suggest that hTID1 functions as an important cell death regulator and raise the interesting possibility that hTID1 could exert tumor suppressor activity.
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Abbreviations
- AICD:
-
activation-induced cell death
- CHX:
-
cycloheximide
- ER:
-
endoplasmic reticulum
- FBS:
-
fetal bovine serum
- IF:
-
immunofluorescence microscopy
- MMC:
-
mitomycin c
- RNAi:
-
RNA interference
- PAGE:
-
polyacrylamide gel electrophoresis
- PBS:
-
phosphate-buffered saline
- siRNA:
-
double-stranded small inhibitory RNAi
- TNFα:
-
tumor necrosis factor alpha
- TRAIL:
-
TNF-related apoptosis-inducing ligand
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Acknowledgements
We are grateful to C Suzuki for the TidS- and TidL-specific polyclonal antisera, to Y Shi for the pBS/U6 vector designed for DNA-based RNAi and to S Korsmeyer for the pcDNA3 vector encoding tBID. This work was supported by Public Health Services Grants CA-81135 and HL56949 to KM.
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Edwards, K., Münger, K. Depletion of physiological levels of the human TID1 protein renders cancer cell lines resistant to apoptosis mediated by multiple exogenous stimuli. Oncogene 23, 8419–8431 (2004). https://doi.org/10.1038/sj.onc.1207732
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DOI: https://doi.org/10.1038/sj.onc.1207732
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