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O-GlcNAc transferase regulates p21 protein levels and cell proliferation through the FoxM1–Skp2 axis in a p53-independent manner
Journal of Biological Chemistry ( IF 5.5 ) Pub Date : 2022-07-20 , DOI: 10.1016/j.jbc.2022.102289
Rafaela Muniz de Queiroz 1 , Sung-Hwan Moon 1 , Carol Prives 1
Affiliation  

The protein product of the CDKN1A gene, p21, has been extensively characterized as a negative regulator of the cell cycle. Nevertheless, it is clear that p21 has manifold complex and context-dependent roles that can be either tumor suppressive or oncogenic. Most well studied as a transcriptional target of the p53 tumor suppressor protein, there are other means by which p21 levels can be regulated. In this study, we show that pharmacological inhibition or siRNA-mediated reduction of O-GlcNAc transferase (OGT), the enzyme responsible for glycosylation of intracellular proteins, increases expression of p21 in both p53-dependent and p53-independent manners in nontransformed and cancer cells. In cells harboring WT p53, we demonstrate that inhibition of OGT leads to p53-mediated transactivation of CDKN1A, while in cells that do not express p53, inhibiting OGT leads to increased p21 protein stabilization. p21 is normally degraded by the ubiquitin-proteasome system following ubiquitination by, among others, the E3 ligase Skp-Cullin-F-box complex; however, in this case, we show that blocking OGT causes impairment of the Skp-Cullin-F-box ubiquitin complex as a result of disruption of the FoxM1 transcription factor–mediated induction of Skp2 expression. In either setting, we conclude that p21 levels induced by OGT inhibition correlate with cell cycle arrest and decreased cancer cell proliferation.



中文翻译:

O-GlcNAc 转移酶通过 FoxM1-Skp2 轴以不依赖 p53 的方式调节 p21 蛋白水平和细胞增殖

CDKN1A 基因的蛋白质产物 p21 已被广泛表征为细胞周期的负调节剂。然而,很明显 p21 具有多种复杂且依赖于环境的作用,可以抑制肿瘤或致癌。作为 p53 肿瘤抑制蛋白的转录靶点进行了最充分的研究,还有其他方法可以调节 p21 水平。在这项研究中,我们表明药理学抑制或 siRNA 介导的O-GlcNAc 转移酶 (OGT) 是负责细胞内蛋白质糖基化的酶,它在非转化细胞和癌细胞中以 p53 依赖性和 p53 非依赖性方式增加 p21 的表达。在携带 WT p53 的细胞中,我们证明抑制 OGT 会导致 p53 介导的 CDKN1A 反式激活,而在不表达 p53 的细胞中,抑制 OGT 会导致 p21 蛋白稳定性增加。p21 通常在被 E3 连接酶 Skp-Cullin-F-box 复合物泛素化后被泛素-蛋白酶体系统降解;然而,在这种情况下,我们发现阻断 OGT 会导致 Skp-Cullin-F-box 泛素复合物受损,这是由于 FoxM1 转录因子介导的 Skp2 表达诱导的破坏。在任何一种情况下,

更新日期:2022-07-20
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