Abstract
Tribbles homolog 3 (TRIB3) is a scaffold protein activated under hypoxic conditions and involved in several cell survival and proliferation pathways. Recently, we reported opposite associations of TRIB3 mRNA and protein with breast cancer prognosis. In this study, we investigated this discrepancy between TRIB3 mRNA and protein in human breast cancer. We provide several lines of evidence demonstrating that TRIB3 is a stabile protein which levels are not controlled by rapid protein breakdown. Interestingly, we were able to show that during anoxia TRIB3 mRNA translation was profoundly inhibited. Hypoxia induced micro RNA 24 was not responsible for the translational repression of TRIB3. Furthermore miRNA-24 expression levels in breast cancer patient specimens showed no correlation with TRIB3 mRNA or TRIB3 protein levels, or with prognosis. Thus, the expression of miRNA-24 does not explain the difference between mRNA and protein expression of TRIB3 in this cohort of breast cancer patients. In conclusion, TRIB3 protein is a stable protein which levels are predominantly regulated by translational control of TRIB3 mRNA transcript.
Highlights
Tribbles homolog 3 (TRIB3) is a protein involved in multiple signaling pathways, including MAPK [1], TGF-beta [2,3], NFkB [4,5] and the PI3K pathway [6]
It has been described that patients with tumors that express more TRIB3 mRNA exhibit a poor prognosis [7,8,9], whereas in patients tumors with high levels of TRIB3 protein as established by immunohistochemistry were associated with a good prognosis [9,10]
The important role for TRIB3 in cell survival under hypoxic conditions was indicated by the observation that after knockdown of TRIB3 cell survival was increased under hypoxia
Summary
Tribbles homolog 3 (TRIB3) is a protein involved in multiple signaling pathways, including MAPK [1], TGF-beta [2,3], NFkB [4,5] and the PI3K pathway [6]. TRIB3 mRNA levels are upregulated by a variety of stresses, including hypoxia [7]. It is found that high TRIB3 mRNA expression is associated with a poor prognosis in both breast cancer and colon cancer [7,8,9]. In the same group of breast cancer patients we found that TRIB3 protein expression had an opposite relation with prognosis [9]. High TRIB3 protein expression denotes a good prognosis. In oral tongue squamous cell carcinomas it was found that TRIB3 protein expression was associated with a good prognosis [10]
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