Multifaceted role for p53 in pancreatic cancer suppression

克拉斯 胰腺上皮内瘤变 癌症研究 生物 细胞生长 胰腺癌 癌症 结直肠癌 遗传学
作者
Stephano S. Mello,Brittany M. Flowers,Pawel K. Mazur,James J. Lee,Fabian Müller,Sarah K. Denny,Sofia Ferreira,Kathryn J. Hanson,Seung K. Kim,William J. Greenleaf,Laura D. Wood,Laura D. Attardi
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [Proceedings of the National Academy of Sciences]
卷期号:120 (10) 被引量:3
标识
DOI:10.1073/pnas.2211937120
摘要

The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53’s critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant—p53 53,54 —which we previously showed is a more robust PDAC suppressor than wild-type p53, to elucidate how p53 acts at the cellular level to dampen PDAC development. Using both inflammation-induced and KRAS G12D -driven PDAC models, we find that p53 53,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. Moreover, p53 53,54 suppresses KRAS signaling in PanINs and limits effects on the extracellular matrix (ECM) remodeling. While p53 53,54 has highlighted these functions, we find that pancreata in wild-type p53 mice similarly show less ADM, as well as reduced PanIN cell proliferation, KRAS signaling, and ECM remodeling relative to Trp53 -null mice. We find further that p53 enhances chromatin accessibility at sites controlled by acinar cell identity transcription factors. These findings reveal that p53 acts at multiple stages to suppress PDAC, both by limiting metaplastic transformation of acini and by dampening KRAS signaling in PanINs, thus providing key new understanding of p53 function in PDAC.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
刚刚
希望天下0贩的0应助HGalong采纳,获得10
刚刚
赘婿应助monica01010采纳,获得10
1秒前
渭水飞熊发布了新的文献求助10
1秒前
白小白完成签到,获得积分10
2秒前
2秒前
索谓完成签到 ,获得积分10
2秒前
2秒前
lqy发布了新的文献求助10
3秒前
闪闪的璎发布了新的文献求助10
3秒前
承蒙大爱完成签到 ,获得积分10
4秒前
无花果应助王淳采纳,获得10
4秒前
4秒前
超级冰薇发布了新的文献求助10
4秒前
科研通AI2S应助超级的抽屉采纳,获得10
5秒前
李爱国应助超级的抽屉采纳,获得30
5秒前
Xxynysmhxs完成签到 ,获得积分10
5秒前
5秒前
sci_sci完成签到,获得积分20
5秒前
6秒前
6秒前
田様应助缓慢念云采纳,获得10
7秒前
7秒前
winghy发布了新的文献求助10
8秒前
华仔应助杨洪宇采纳,获得10
8秒前
梦丽有人完成签到,获得积分10
9秒前
10秒前
rocket完成签到,获得积分10
11秒前
111111应助呆萌的垣采纳,获得30
11秒前
11秒前
充电宝应助鱼小汤圆采纳,获得10
12秒前
桔梗完成签到,获得积分10
13秒前
joshua发布了新的文献求助30
13秒前
奥利奥发布了新的文献求助10
13秒前
李傲发布了新的文献求助10
13秒前
QXS完成签到,获得积分10
14秒前
14秒前
15秒前
15秒前
高分求助中
Evolution 3rd edition 1500
Lire en communiste 1000
Mantiden: Faszinierende Lauerjäger Faszinierende Lauerjäger 700
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 700
Elastic local buckling behaviour of corroded cold-formed steel columns 500
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
2-Acetyl-1-pyrroline: an important aroma component of cooked rice 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3180500
求助须知:如何正确求助?哪些是违规求助? 2830796
关于积分的说明 7981033
捐赠科研通 2492477
什么是DOI,文献DOI怎么找? 1329555
科研通“疑难数据库(出版商)”最低求助积分说明 635745
版权声明 602954