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Dihydropyrimidinase like 3 as a novel target of wild type p53 suppresses MAPK pathway in response to hypoxia

YUANNA DU1,#, WENWEN GONG2,#, JING LIANG1,#, RUKUN ZANG1, JUNJUN MOU1
1 Department of Radiotherapy, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, China
2 Department of Obstetrics, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, 264000, China
* Address correspondence to: Rukun Zang, ; Junjun Mou,
# Authors contribute equally to this work
(This article belongs to this Special Issue: Cellular Biomechanics in Health and Diseases)

BIOCELL 2022, 46(5), 1181-1188. https://doi.org/10.32604/biocell.2022.016148

Received 10 February 2021; Accepted 06 April 2021; Issue published 06 January 2022

Abstract

Endometrial cancer remains to be a major type of malignancy in threatening female life. Molecular insights in advancing our understanding of endometrial tumorigenesis are much needed. We here report that a less-studied protein Dihydropyrimidinase like 3 (DPYSL3) is a potent tumor suppressor. DPYSL3 is uniquely regulated by wild type p53 (wtp53), and its expression is at the highest level when cells carry wtp53 and are exposed to hypoxia. We reveal that wtp53 can bind DPYSL3 promoter to enhance DPYSL3 expression and in turn, the elevated DPYSL3 can restrain cancer cell proliferation and invasion in vitro and in vivo. Importantly, we observe that DPYSL3 can interfere with MAP kinase pathway, supported by a substantially reduced level of phosphorylated ERK in cells with high expression of DPYSL3. Furthermore, we identify the specific region of DPYSL3 that is responsible for its interaction with MEK and a subsequently reduced activity of ERK. In combination of molecular docking and mutagenesis analysis, we validated that the therapeutic implication of 17 A.A.s of DPYSL3, which can reduce the activity of the MAPK pathway and inhibit endometrial tumor cell growth in vitro and in vivo. Therefore, our study not only demonstrates in-depth understanding of human tumorigenesis, especially endometrial tumor, but also only provides a therapeutic potential to develop an effective tool to fight against human malignancy.

Keywords

DPYSL3; Hypoxia; p53; MAPK; Endometrial cancer

Cite This Article

DU, Y., GONG, W., LIANG, J., ZANG, R., MOU, J. (2022). Dihydropyrimidinase like 3 as a novel target of wild type p53 suppresses MAPK pathway in response to hypoxia. BIOCELL, 46(5), 1181–1188.



This work is licensed under a Creative Commons Attribution 4.0 International License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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