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Characterization of novel transforming growth factor-beta type I receptors found in malignant pleural effusion tumor
Kuo-Li Chen1, Wan-Hsin Liu, Yi-Yuan Yang
1Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan. corry@nhri.org.tw
Background:
Tumors expressing a transforming growth factor-beta type I receptor (T beta RI) mutant with sequence deletions in a nine-alanine (9A) stretch of the signal peptide are reported to be highly associated with disease progression. Expression of this mutant could interfere with endogenous TGFbeta signaling in the cell. However, little is known about the importance of the remaining part of the signal peptide on the cellular function of T beta RI.
Results:
We cloned and identified four new in-frame deletion variants of T beta RI, designated DM1 to DM4, in pleural effusion-derived tumor cells. Intriguingly, DM1 and DM2, with a small region truncated in the putative signal peptide of T beta RI, had a serious defect in their protein expression compared with that of the wild-type receptor. Using serial deletion mutagenesis, we characterized a region encoded by nucleotides 16-51 as a key element controlling T beta RI protein expression. Consistently, both DM1 and DM2 have this peptide deleted. Experiments using cycloheximde and MG132 further confirmed its indispensable role for the protein stability of T beta RI. In contrast, truncation of the 9A-stretch itself or a region downstream to the stretch barely affected T beta RI expression. However, variants lacking a region C-terminal to the stretch completely lost their capability to conduct TGFbeta-induced transcriptional activation. Intriguingly, expression of DM3 in a cell sensitive to TGFbeta made it significantly refractory to TGFbeta-mediated growth inhibition. The effect of DM3 was to ablate the apoptotic event induced by TGFbeta.
Conclusion:
We identified four new transcript variants of T beta RI in malignant effusion tumor cells and characterized two key elements controlling its protein stability and transcriptional activation. Expression of one of variants bestowed cancer cells with a growth advantage in the presence of TGFbeta. These results highlight the potential roles of some naturally occurring T beta RI variants on the promotion of tumor malignancy.
Insights
New transforming growth factor-beta type I receptor (T beta RI) variants were found in tumors. Some variants impact T beta RI protein stability and TGF-beta signaling, potentially promoting tumor growth.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Transforming growth factor-beta type I receptor (T beta RI) mutants with deletions in the nine-alanine (9A) stretch of the signal peptide are linked to tumor progression.
- The role of other signal peptide regions in T beta RI function remains largely unknown.
Purpose of the Study:
- To identify and characterize novel T beta RI variants in tumor cells.
- To investigate the functional impact of signal peptide variations on T beta RI protein expression, stability, and TGF-beta signaling.
Main Methods:
- Cloning and identification of T beta RI deletion variants (DM1-DM4) from pleural effusion tumor cells.
- Serial deletion mutagenesis to map key functional regions within the T beta RI signal peptide.
- Analysis of protein expression, stability (using cycloheximide and MG132), and TGF-beta-induced transcriptional activation.
Main Results:
- Four new in-frame deletion variants (DM1-DM4) of T beta RI were identified.
- Variants DM1 and DM2, lacking a specific region (nucleotides 16-51) in the signal peptide, showed significantly reduced protein expression and stability.
- A C-terminal region downstream of the 9A-stretch was crucial for TGF-beta-induced transcriptional activation; its absence abolished this function.
- Variant DM3 conferred resistance to TGF-beta-mediated growth inhibition and apoptosis in sensitive cells.
Conclusions:
- Naturally occurring T beta RI variants can significantly alter receptor expression, stability, and signaling.
- Specific T beta RI variants identified in malignant effusions may contribute to tumor progression by enhancing cancer cell survival and growth in a TGF-beta-rich environment.
- These findings underscore the potential role of T beta RI variants in promoting tumor malignancy.
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