Overexpression of Pdx1, reduction of p53, or deletion of CHOP attenuates pancreas hypoplasia in mice with pancreas-specific O-GlcNAc transferase deletion.
Overexpression of Pdx1, reduction of p53, or deletion of CHOP attenuates pancreas hypoplasia in mice with pancreas-specific O-GlcNAc transferase deletion.
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DOI：
10.1016/j.jbc.2023.102878
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发表时间：
2023-02
影响因子：
4.8
通讯作者：
Alejandro, Emilyn U.
中科院分区：
文献类型：
--
作者：
Wong, Alicia;Pritchard, Samantha;Moore, Mackenzie;Akhaphong, Brian;Avula, Nandini;Beetch, Megan;Fujitani, Yoshio;Alejandro, Emilyn U.
胰腺上皮祖细胞中O-GlcNAc转移酶（Ogt）的缺失导致出生时胰腺发育不全，部分原因是胚胎发育过程中细胞凋亡增加。β细胞中Ogt的组成性缺失导致内质网应激和凋亡增加，而在Ogt缺乏的胰腺中，转录组学数据先前显示，肿瘤抑制蛋白p53和胰腺十二指肠同源盒1 （Pdx1）是发育中胰腺中关键的细胞存活蛋白，是差异表达基因的上游调节因子。然而，这些基因在胰腺发育不全中的具体作用尚不清楚。在本研究中，我们探讨了p53、内质网应激蛋白CHOP和Pdx1在胰腺发育中的独立作用，以及它们在Ogt缺失背景下胰腺发育不全的功能修复中的应用。通过体内遗传操作和形态计量学分析，我们发现Ogt在胰腺发育中起着关键的调节作用。杂合子缺失而非纯合子缺失胰腺p53对β-细胞、α-细胞和外分泌细胞团块有部分拯救作用，而CHOP的全身缺失对胰腺重量有部分拯救作用，对外分泌细胞团块有完全拯救作用。然而，这两种方法都不足以完全减轻出生时ogt缺乏胰腺的胰腺发育不全。此外，在Ogt缺失的背景下，胰腺上皮中Pdx1的过表达导致胰腺重量和β细胞质量的部分恢复。这些发现通过靶向胰腺发育中的转录因子Pdx1和p53等多种蛋白质，强调了Ogt在胰腺发育中的必要性。
Deletion of O-GlcNAc transferase (Ogt) in pancreatic epithelial progenitor cells results in pancreatic hypoplasia at birth, partly due to increased apoptosis during embryonic development. Constitutive loss of Ogt in β-cells results in increased ER stress and apoptosis, and in the Ogt-deficient pancreas, transcriptomic data previously revealed both tumor suppressor protein p53 and pancreatic duodenal homeobox 1 (Pdx1), key cell survival proteins in the developing pancreas, as upstream regulators of differentially expressed genes. However, the specific roles of these genes in pancreatic hypoplasia are unclear. In this study, we explored the independent roles of p53, ER stress protein CHOP, and Pdx1 in pancreas development and their use in the functional rescue of pancreatic hypoplasia in the context of Ogt loss. Using in vivo genetic manipulation and morphometric analysis, we show that Ogt plays a key regulatory role in pancreas development. Heterozygous, but not homozygous, loss of pancreatic p53 afforded a partial rescue of β-cell, α-cell, and exocrine cell masses, while whole body loss of CHOP afforded a partial rescue in pancreas weight and a full rescue in exocrine cell mass. However, neither was sufficient to fully mitigate pancreatic hypoplasia at birth in the Ogt-deficient pancreas. Furthermore, overexpression of Pdx1 in the pancreatic epithelium resulted in partial rescues in pancreas weight and β-cell mass in the Ogt loss background. These findings highlight the requirement of Ogt in pancreas development by targeting multiple proteins such as transcription factor Pdx1 and p53 in the developing pancreas.
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DOI：
10.1083/jcb.201501101
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bond MR;Hanover JA
通讯作者：
Hanover JA
影响因子：
8.8
作者：
Alejandro EU;Bozadjieva N;Kumusoglu D;Abdulhamid S;Levine H;Haataja L;Vadrevu S;Satin LS;Arvan P;Bernal-Mizrachi E
通讯作者：
Bernal-Mizrachi E
DOI：
10.1038/nrgastro.2013.36
发表时间：
2013-06
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.2
作者：
Araki, E;Oyadomari, S;Mori, M
通讯作者：
Mori, M
影响因子：
9.2
作者：
JACKS, T;REMINGTON, L;WEINBERG, RA
通讯作者：
WEINBERG, RA