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Int J Med Sci 2022; 19(3):525-536. doi:10.7150/ijms.68385 This issue Cite

Research Paper

RIP1-dependent Apoptosis and Differentiation Regulated by Skp2 and Akt/GSK3β in Acute Myeloid Leukemia

Wenran Dan1,2, Liang Zhong2, Zhonghui Zhang1, Peng Wan1,2, Yang Lu1, Xiao Wang1, Zhenyan Liu1, Xuan Chu1,2, Beizhong Liu1,2✉

1. Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China.
2. Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.

✉ Corresponding author: Beizhong Liu, Central Laboratory of Yong-Chuan Hospital, Chongqing Medical University, Chongqing 402160, China. E-mail: Liubeizhongedu.cn; Fax number: 0086-023-85368122.

Citation:
Dan W, Zhong L, Zhang Z, Wan P, Lu Y, Wang X, Liu Z, Chu X, Liu B. RIP1-dependent Apoptosis and Differentiation Regulated by Skp2 and Akt/GSK3β in Acute Myeloid Leukemia. Int J Med Sci 2022; 19(3):525-536. doi:10.7150/ijms.68385. https://www.medsci.org/v19p0525.htm
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Abstract

Graphic abstract

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by variations in cytogenetics and molecular abnormalities, which result in variable response to therapy. Receptor-interacting serine/threonine kinase 1 (RIP1)-mediated necroptosis has been reported to have a potential role in the treatment of AML. We obtained Skp2 and RIP1 are significantly overexpressed in AML samples using original published data, and identified that Skp2-depletion in AML cells significantly suppressed RIP1. Functional analysis showed that the inhibition of RIP1 caused by necrostatin-1 (Nec-1) inhibited the proliferation, simultaneously facilitate both the apoptosis and differentiation of AML cells. Mechanistical analysis elucidated that knockdown of Skp2 suppresses RIP1 by transcriptional regulation but not by proteasome degradation. Additionally, Skp2 regulated the function of RIP1 by decreasing K63-linked ubiquitin interaction with RIP1. Moreover, the suppression of Akt/GSK3β was observed in Skp2 knockdown stable NB4 cells. Also, GSK3β inactivation via small-molecule inhibitor treatment remarkably decreased RIP1 level. RIP1 regulates differentiation by interacting with RARα, increasing RA signaling targets gene C/EBPα and C/EBPβ. In conclusion, our study provides a novel insight into the mechanism of tumorigenesis and the development of AML, for which the Skp2-Akt/GSK3β-RIP1 pathway can be developed as a promising therapeutic target.

Keywords: Skp2, RIP1, GSK3β, Acute myelocytic leukemia

Citation styles

APA
Dan, W., Zhong, L., Zhang, Z., Wan, P., Lu, Y., Wang, X., Liu, Z., Chu, X., Liu, B. (2022). RIP1-dependent Apoptosis and Differentiation Regulated by Skp2 and Akt/GSK3β in Acute Myeloid Leukemia. International Journal of Medical Sciences, 19(3), 525-536. https://doi.org/10.7150/ijms.68385.

ACS
Dan, W.; Zhong, L.; Zhang, Z.; Wan, P.; Lu, Y.; Wang, X.; Liu, Z.; Chu, X.; Liu, B. RIP1-dependent Apoptosis and Differentiation Regulated by Skp2 and Akt/GSK3β in Acute Myeloid Leukemia. Int. J. Med. Sci. 2022, 19 (3), 525-536. DOI: 10.7150/ijms.68385.

NLM
Dan W, Zhong L, Zhang Z, Wan P, Lu Y, Wang X, Liu Z, Chu X, Liu B. RIP1-dependent Apoptosis and Differentiation Regulated by Skp2 and Akt/GSK3β in Acute Myeloid Leukemia. Int J Med Sci 2022; 19(3):525-536. doi:10.7150/ijms.68385. https://www.medsci.org/v19p0525.htm

CSE
Dan W, Zhong L, Zhang Z, Wan P, Lu Y, Wang X, Liu Z, Chu X, Liu B. 2022. RIP1-dependent Apoptosis and Differentiation Regulated by Skp2 and Akt/GSK3β in Acute Myeloid Leukemia. Int J Med Sci. 19(3):525-536.

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