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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Testes-specific protease 50 promotes cell proliferation via inhibiting activin signaling
1National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China.
Abstract:
Testes-specific protease 50 (TSP50), a novelly identified oncogene, has the capacity to induce cell proliferation, cell invasion and tumor growth. Further studies indicated that CAGA-luc (an activin-responsive reporter construct) reporter activity could be significantly suppressed by TSP50 overexpression, implying that the activin signaling may participate in TSP50-mediated cell proliferation. Here, we reported that TSP50 had an inhibitory effect on activin signaling. Mechanistic studies revealed that TSP50 could interact with ActRIIA, inhibit activin typeIreceptor (ActRIB) phosphorylation, repress Smad2/3 nuclear accumulation and finally promote cell proliferation by reducing the expression of activin signal target gene p27. Additionally, we found that ActRIB activation could reverse TSP50-mediated cell proliferation and tumor growth. Furthermore, analysis of human breast cancer specimens by immunohistochemistry indicated that TSP50 expression was negatively related to p-Smad2/3 and p27 protein levels. Most importantly, breast cancer diagnosis-related indicators such as tumor size, tumor grade, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) levels, were correlated well with TSP50/p-Samd2/3 and TSP50/p27 expression status. Thus, our studies revealed a novel regulatory mechanism underlying TSP50-induced cell proliferation and provided a new favorable intervention target for the treatment of breast cancer.
Insights
Testes-specific protease 50 (TSP50) oncogene promotes breast cancer by inhibiting activin signaling. TSP50 overexpression reduces p27 levels, driving cell proliferation and tumor growth, offering a new therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Testes-specific protease 50 (TSP50) is a newly identified oncogene.
- TSP50 is known to promote cell proliferation, invasion, and tumor growth.
- TSP50 overexpression suppresses activin signaling, suggesting its involvement in proliferation.
Purpose of the Study:
- To investigate the inhibitory effect of TSP50 on activin signaling.
- To elucidate the molecular mechanisms by which TSP50 influences cell proliferation.
- To explore the therapeutic potential of targeting TSP50 in breast cancer.
Main Methods:
- Investigated TSP50 interaction with ActRIIA and ActRIB phosphorylation.
- Analyzed Smad2/3 nuclear accumulation and p27 expression.
- Utilized immunohistochemistry on human breast cancer specimens.
- Correlated TSP50 expression with clinical indicators (tumor size, grade, ER, PR, HER-2).
Main Results:
- TSP50 interacts with ActRIIA, inhibiting ActRIB phosphorylation and Smad2/3 nuclear accumulation.
- TSP50 reduces p27 expression, promoting cell proliferation and tumor growth.
- Activation of ActRIB reverses TSP50-mediated proliferation and tumor growth.
- TSP50 expression inversely correlates with p-Smad2/3 and p27 levels in breast cancer.
- TSP50/p-Smad2/3 and TSP50/p27 expression correlates with breast cancer diagnostic indicators.
Conclusions:
- TSP50 inhibits activin signaling, leading to reduced p27 expression and promoting cell proliferation.
- TSP50 plays a significant role in breast cancer progression.
- Targeting TSP50 or its downstream effectors presents a promising therapeutic strategy for breast cancer.
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