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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Spleen Tyrosine Kinase Inhibition Modulates p53 Activity
1Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
Abstract:
Spleen tyrosine kinase (SYK) is a cytoplasmic enzyme that promotes survival and proliferation of B cells. SYK inhibition has shown promising results in the treatment of arthritis and chronic lymphocytic leukemia (CLL). However, in other context, it has been shown that SYK overexpression in epithelial cancer cells induced senescence in p53-dependent mechanism, which underscored its antineoplastic activity in vitro. Here, we show that SYK was induced in response of DNA damage in parallel with p53 levels. In addition, using chemical inhibitors of SYK reduced p53 levels in HCT116 and HT1080 cell lines, which underlines the role of SYK inhibition on p53 activity. Furthermore, SYK inhibition modulated the cell growth, which resulted in a decreasing in cell death. Interestingly, SYK expression showed a positive prognosis in patients with solid tumors in correlations with their survival rates, as expected negative correlation was seen between SYK expression and survival rate of patients with CLL. In conclusion, these findings demonstrate that SYK inhibition modulates p53 expression and activity in HCT116 and HT1080 cells. Reconsidering using of SYK inhibitors in clinical setting in the future should be evaluated carefully in accordance with these findings to prevent the formation of secondary malignancies.
Insights
Spleen tyrosine kinase (SYK) inhibition impacts p53 levels and cell death. Careful evaluation of SYK inhibitors is needed to prevent secondary malignancies, especially in solid tumors and chronic lymphocytic leukemia (CLL).
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Signaling
Background:
- Spleen tyrosine kinase (SYK) promotes B cell survival and proliferation, with inhibition showing promise in arthritis and chronic lymphocytic leukemia (CLL).
- SYK overexpression in epithelial cancers can induce p53-dependent senescence, suggesting antineoplastic activity.
Purpose of the Study:
- To investigate the role of SYK in DNA damage response and its impact on p53 activity.
- To evaluate the effect of SYK inhibition on cell growth, cell death, and patient prognosis in solid tumors and CLL.
Main Methods:
- Utilized chemical inhibitors of SYK in HCT116 and HT1080 cell lines.
- Assessed SYK and p53 levels following DNA damage.
- Correlated SYK expression with survival rates in solid tumor and CLL patient cohorts.
Main Results:
- SYK is induced upon DNA damage, paralleling p53 levels.
- SYK inhibition reduced p53 levels and modulated cell growth, decreasing cell death.
- SYK expression correlated positively with survival in solid tumors but negatively in CLL patients.
Conclusions:
- SYK inhibition modulates p53 expression and activity in specific cell lines.
- Clinical use of SYK inhibitors requires careful consideration due to potential effects on cell death and secondary malignancy risk, particularly in solid tumors versus CLL.
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