Characterization of novel transforming growth factor-beta type I receptors found in malignant pleural effusion tumor cells

被引:3
作者
Chen, Kuo-Li
Liu, Wan-Hsin
Yang, Yi-Yuan
Leu, Sy-Jye C.
Shih, Neng-Yao [1 ]
机构
[1] Natl Inst Canc Res, Natl Hlth Res Inst, Taipei 114, Taiwan
[2] Natl Def Med Ctr, Grad Inst Life Sci, Taipei 114, Taiwan
[3] Taipei Med Univ, Sch Med Lab Sci & Biotechnol, Taipei 110, Taiwan
[4] Taipei Med Univ, Grad Inst Cell & Mol Biol, Taipei 110, Taiwan
来源
BMC MOLECULAR BIOLOGY | 2007年 / 8卷
关键词
TGF-BETA; CANCER; SIGNAL; GENE; RNA; TGFBR1-ASTERISK-6A; SUSCEPTIBILITY; IDENTIFICATION; POLYMORPHISM; DEGRADATION;
D O I
10.1186/1471-2199-8-72
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 TGF beta 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 TGF beta-induced transcriptional activation. Intriguingly, expression of DM3 in a cell sensitive to TGF beta made it significantly refractory to TGF beta-mediated growth inhibition. The effect of DM3 was to ablate the apoptotic event induced by TGF beta. 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 TGF beta. These results highlight the potential roles of some naturally occurring T beta RI variants on the promotion of tumor malignancy.
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页数:15
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