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Truncated forms of RUNX3 Unlike Full Length Protein Alter Cell Proliferation in a TGF-β Context Dependent Manner
Narges Rahmanian1, Parastoo Tarighi2, Mehdi Gharghabi3
1Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Abstract:
The Runt related transcription factors (RUNX) are recognized as key players in suppressing or promoting tumor growth. RUNX3, a member of this family, is known as a tumor suppressor in many types of cancers, although such a paradigm was challenged by some researchers. The TGF-β pathway governs major upstream signals to activate RUNX3. RUNX3 protein consists of several regions and domains. The Runt domain is a conserved DNA binding domain and is considered as the main part of RUNX proteins. Herein, we compared the effects of Runt domains and full-Runx3 in cell viability by designing two constructs of Runx3, including N-terminal region and Runt domain. We investigated the effect of full-Runx3, N-t, and RD on growth inhibition in AGS, MCF-7, A549, and HEK293 cell lines which are different in TGF-β sensitivity, in the absence and presence of TGF-β. The full length RUNX3 did not notably inhibit growth of these cell lines while, the N-t and RD truncates showed different trends in these cell lines. Cell proliferation in the TGF-β impaired context cell lines (AGS and MCF-7) significantly decrease while in the A549 significantly increase. On the other hand, transfection of N-t and RD did not considerably affect the cell proliferation in the HEK293.Our results show that full-lenght RUNX3 did not affect the cell viability. Conversely, the N-t and RD constructs significantly changed cell proliferation. Therefore, therapeutic potentials for these truncated proteins are suggested in tumors with RUNX proteins dysfunction, even in the TGF-β impair context.
Insights
The full-length RUNX3 protein did not impact cell viability, but its truncated forms, N-terminal (N-t) and Runt domain (RD), altered cell proliferation. These RUNX3 truncates show therapeutic potential for tumors with RUNX dysfunction.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Runt-related transcription factors (RUNX) are crucial in cancer, with RUNX3 often acting as a tumor suppressor.
- The transforming growth factor-beta (TGF-β) pathway is a key regulator of RUNX3 activity.
- RUNX3 protein has distinct functional domains, including the DNA-binding Runt domain.
Purpose of the Study:
- To investigate the differential effects of full-length RUNX3 and its truncated constructs (N-terminal region and Runt domain) on cell viability.
- To assess these effects across various cancer cell lines with differing TGF-β pathway sensitivity.
- To explore the therapeutic potential of RUNX3 truncates in cancer treatment.
Main Methods:
- Constructing and transfecting cells with full-length RUNX3, N-terminal (N-t), and Runt domain (RD) RUNX3 variants.
- Evaluating cell proliferation and viability in AGS, MCF-7, A549, and HEK293 cell lines.
- Analyzing the impact of TGF-β presence or absence on cell responses to RUNX3 variants.
Main Results:
- Full-length RUNX3 did not significantly inhibit cell growth in the tested cell lines.
- The N-t and RD RUNX3 constructs exhibited varied effects on cell proliferation depending on the cell line and TGF-β sensitivity.
- Specifically, proliferation decreased in TGF-β-impaired cells (AGS, MCF-7) and increased in A549 cells, while HEK293 cells showed minimal change.
Conclusions:
- Cellular responses to RUNX3 are domain-dependent, with truncates having significant effects where the full protein does not.
- RUNX3 truncates demonstrate potential for therapeutic applications in cancers with RUNX protein dysfunction, irrespective of TGF-β pathway status.
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