更新于：2024-05-01

Redd1

DNA损伤诱导转录因子4

更新于：2024-05-01

基本信息

别名

DDIT4、Dig2、DNA damage inducible transcript 4

+ [9]

简介

Regulates cell growth, proliferation and survival via inhibition of the activity of the mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 is mediated by a pathway that involves DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. Plays an important role in responses to cellular energy levels and cellular stress, including responses to hypoxia and DNA damage. Regulates p53/TP53-mediated apoptosis in response to DNA damage via its effect on mTORC1 activity. Its role in the response to hypoxia depends on the cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes, but not in hepatocytes (By similarity). Required for mTORC1-mediated defense against viral protein synthesis and virus replication (By similarity). Inhibits neuronal differentiation and neurite outgrowth mediated by NGF via its effect on mTORC1 activity. Required for normal neuron migration during embryonic brain development. Plays a role in neuronal cell death.

关联

项与 Redd1 相关的药物

PF-4523655

靶点

Redd1

作用机制

Redd1抑制剂 [+1]

在研机构

Pfizer Inc. [+1]

原研机构

Silence Therapeutics Plc

在研适应症

糖尿病性黄斑水肿 [+1]

非在研适应症

年龄相关性黄斑变性 [+2]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 Redd1 相关的临床试验

NCT01445899 / Completed临床2期

An Open-Label Dose Escalation Study of PF-04523655 (Stratum I) Combined With a Prospective, Randomized, Double-Masked, Multi-Center, Controlled Study (Stratum II) Evaluating the Efficacy and Safety of PF-04523655 Alone and in Combination With Ranibizumab Versus Ranibizumab Alone in Diabetic Macular Edema (MATISSE STUDY)

This is a two-part study. The first part (Stratum I) is an open-label, dose escalation, safety, tolerability and pharmacokinetic study, where active study drug (PF-04523655) will be given to all patients who participate. Stratum I will determine the maximum tolerated dose and any dose-limiting toxicities. The second part (Stratum II) is a prospectively randomized, multi-center, double-masked, dose ranging study evaluating the efficacy and safety of PF-04523655 alone and in combination with ranibizumab versus ranibizumab alone in patients with DME.

开始日期2012-02-01

申办/合作机构

Quark Pharmaceuticals, Inc.

NCT00713518 / Completed临床2期

Phase II Open Label Multicenter, Prospective, Randomized, Age Related Macular Degeneration, Comparator Controlled Study Evaluating PF-04523655 Versus Ranibizumab In The Treatment Of Subjects With Choroidal Neovascularization (MONET Study).

The aim of the study is to evaluate whether PF-04523655 is effective in the treatment of neovascular/wet AMD and at which dose.

开始日期2009-11-01

申办/合作机构

Quark Pharmaceuticals, Inc.

[+1]

EUCTR2008-003210-10-AT / Not yet recruitingN/A

PHASE II OPEN LABEL, MULTICENTER, PROSPECTIVE,RELATED MACULAR DEGENERATION, COMPARATOR STUDY EVALUATING PF-04523655 VERSUS RANIBIZUMAB TREATMENT OF SUBJECTS WITH CHOROIDAL NEOVASCULARIZATION (MONET STUDY)

开始日期2009-09-24

申办/合作机构

Pfizer Inc.

100 项与 Redd1 相关的临床结果

登录后查看更多信息

100 项与 Redd1 相关的转化医学

登录后查看更多信息

0 项与 Redd1 相关的专利（医药）

登录后查看更多信息

739

项与 Redd1 相关的文献（医药）

2024-02-13·American journal of physiology. Gastrointestinal and liver physiology

Mechanisms Driving Fasting-Induced Protection from Genotoxic Injury in the Small Intestine.

Article

作者: Kali Deans-Fielder ; Timothy Wu ; Thanh Nguyen ; Sarah To ; Yang-Zhe Huang ; Steven J Bark ; Jason C Mills ; Noah F Shroyer

Genotoxic agents like doxorubicin (DXR) can cause damage to the intestines that can be ameliorated by fasting. How fasting is protective and the optimal timing of fasting and refeeding remain unclear. Here, our analysis of fasting/refeeding-induced global intestinal transcriptional changes revealed metabolic shifts and implicated the cellular energetic hub mTORC1 in protecting from DXR-induced DNA damage. Our analysis of specific transcripts and proteins in intestinal tissue and tissue extracts showed that fasting followed by refeeding at the time of DXR administration reduced damage and caused a spike in mTORC1 activity. However, continued fasting after DXR prevented the mTORC1 spike and damage reduction. Surprisingly, the mTORC1 inhibitor, rapamycin, did not block fasting/refeeding-induced reduction in DNA damage, suggesting that increased mTORC1 is dispensable for protection against the initial DNA damage response. In Ddit4^-/- mice (DDIT4 functions to regulate mTORC1 activity), fasting reduced DNA damage and increased intestinal crypt viability versus ad libitum-fed Ddit4^-/- mice. Fasted/refed Ddit4^-/- mice maintained body weight, with increased crypt proliferation by 5 days post-DXR, while ad libitum-fed Ddit4^-/- mice continued to lose weight and displayed limited crypt proliferation. Genes encoding epithelial stem cell and DNA repair proteins were elevated in DXR-injured fasted vs ad libitum Ddit4^-/- intestines. Thus, fasting strongly reduced intestinal damage when normal dynamic regulation of mTORC1 was lost. Overall, the results confirm that fasting protects the intestines against DXR and suggests that fasting works by pleiotropic - including both mTORC1-dependent and independent - mechanisms across the temporally dynamic injury response.

2024-02-01·International wound journal

Integrated genetic analysis of diabetic complications: Bioinformatics insights into foot ulcers, neuropathy and peripheral artery disease.

Article

作者: Jiaru Liang ; Xiaoyang Gong ; Xuyang Hu ; Chong You ; Jiaqi Zhou ; Yuling Gao ; Junwei Zong ; Yong Liu

Diabetic foot ulcers (DFU), diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) are common complications of diabetes mellitus, while diabetic peripheral neuropathy and peripheral arterial disease contribute to the pathogenesis of diabetic foot ulcers, and the pathogenic mechanisms between these three diseases still need further investigation. The keywords 'diabetic foot ulcer', 'diabetic peripheral neuropathy' and 'atherosclerosis' were used to search for related gene sets in the GEO database. Differentially expressed genes (DEGs) were screened and analysed for GO, KEGG and enrichR functional enrichment. Potential three disease biomarkers were identified by SVM-SVM-RFE and LASSO regression analysis. The results were also validated using external datasets and discriminability was measured by area under the ROC curve (AUC). Finally, biomarkers and co-upregulated genes were analysed through the GSEA and Attie Laboratories diabetes databases. A total of 11 shared genes (KRT16, CD24, SAMD9L, SRGAP2, FGL2, GPR34, DDIT4, NFE2L3, FBLN5, ANXA3 and CPA3), two biomarkers (SAMD9L and FGL2) and one co-upregulated gene (CD24) were screened. GO and KEGG pathway analysis of DEGs, enrichr enrichment analysis of shared differential genes and GSEA analysis of biomarkers showed that these significant genes were mainly focused on vasoregulatory, inflammatory-oxidative stress and immunomodulatory pathways. In this study, we used bioinformatics to investigate the intrinsic relationship and potential mechanisms of three common lower extremity complications of diabetes and identified two pivotal genes using the LASSO model and the SVM-RFE algorithm, which will further help clinicians to understand the relationship between diabetic complications, improve the diagnosis and treatment of diabetic foot problems and help doctors to identify the potential risk factors of diabetic foot.

2024-01-13·Cell death & disease

Akt enhances the vulnerability of cancer cells to VCP/p97 inhibition-mediated paraptosis.

Article

作者: Dong Min Lee ; In Young Kim ; Hong Jae Lee ; Min Ji Seo ; Mi-Young Cho ; Hae In Lee ; Gyesoon Yoon ; Jae-Hoon Ji ; Seok Soon Park ; Seong-Yun Jeong ; Eun Kyung Choi ; Yong Hyeon Choi ; Chae-Ok Yun ; Mirae Yeo ; Eunhee Kim ; Kyeong Sook Choi

Valosin-containing protein (VCP)/p97, an AAA+ ATPase critical for maintaining proteostasis, emerges as a promising target for cancer therapy. This study reveals that targeting VCP selectively eliminates breast cancer cells while sparing non-transformed cells by inducing paraptosis, a non-apoptotic cell death mechanism characterized by endoplasmic reticulum and mitochondria dilation. Intriguingly, oncogenic HRas sensitizes non-transformed cells to VCP inhibition-mediated paraptosis. The susceptibility of cancer cells to VCP inhibition is attributed to the non-attenuation and recovery of protein synthesis under proteotoxic stress. Mechanistically, mTORC2/Akt activation and eIF3d-dependent translation contribute to translational rebound and amplification of proteotoxic stress. Furthermore, the ATF4/DDIT4 axis augments VCP inhibition-mediated paraptosis by activating Akt. Given that hyperactive Akt counteracts chemotherapeutic-induced apoptosis, VCP inhibition presents a promising therapeutic avenue to exploit Akt-associated vulnerabilities in cancer cells by triggering paraptosis while safeguarding normal cells.

项与 Redd1 相关的新闻（医药）

2022-09-22

·生物谷

Molecular Cancer: 靶向DDIT4-AS1及其通路可能是治疗胰腺导管腺癌化疗耐药的有效策略

胰腺癌是世界范围内常见的胃肠道恶性肿瘤，具有诊断晚、预后差、死亡率高等特点。胰腺癌目前是癌症相关死亡的第四大原因，5年存活率仅约为10%。胰腺导管腺癌是胰腺癌中最常见的一种。胰腺癌是世界范围内常见的胃肠道恶性肿瘤，具有诊断晚、预后差、死亡率高等特点。胰腺癌目前是癌症相关死亡的第四大原因，5年存活率仅约为10%。胰腺导管腺癌是胰腺癌中最常见的一种。吉西他滨是治疗胰腺癌的一线化疗药物，吉西他滨辅助化疗可显著延长胰腺癌患者的总生存期和无瘤生存期。然而，恶性肿瘤细胞对吉西他滨(GEM)的耐药性显著影响其治疗效果。肿瘤干细胞是导致胰腺癌化疗耐药的重要因素。肿瘤干细胞具有自我更新和多向分化的能力，与肿瘤的耐药、复发和转移密切相关。然而，肿瘤干细胞(CSCs)影响胰腺癌进展和耐药的机制仍然不清楚，还需要进一步的研究。图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-022-01647-0 近日，来自天津医科大学肿瘤研究所的研究人员在Molecular Cancer杂志上发表了题为“The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway”的文章，该研究揭示了ALKBH5介导的m6A修饰导致DDIT4-AS1在胰腺导管腺癌（PDAC）中过表达，DDIT-AS1通过破坏DDIT4的稳定性和激活mTOR通路而增加肿瘤的干性并抑制对GEM的化疗敏感性。靶向DDIT4-AS1及其通路可能是治疗PDAC化疗耐药的有效策略。化疗耐药是导致胰腺癌患者预后不良的主要因素，而肿瘤干细胞是与化疗耐药相关的最关键的因素之一，也是肿瘤治疗的一个非常有前途的方向。然而，肿瘤干性的确切分子机制尚未完全阐明。用M6A-RNA免疫沉淀和测序筛选M6A相关的mRNAs和lncRNAs。采用QRT-PCR和FISH技术分析DDIT4-AS1基因的表达。用球体形成法、集落形成法、Western印迹法和流式细胞术分析PDAC细胞的肿瘤干细胞性和化疗敏感性。通过异种移植实验，分析成瘤率和体内生长情况。通过RNA测序、Western印迹和生物信息学分析确定了DDIT4-AS1的下游途径。IP、RIP和RNA下拉实验检测DDIT4-AS1、DDIT4和UPF1之间的相互作用。建立患者来源的异种移植(PDX)小鼠模型以评估GEM的化疗敏感性。 DDIT4-AS1被确定为ALKBH5的下游靶标之一，而Hur在m6A修饰的位点上的募集对于DDIT4-AS1的稳定是必不可少的。DDIT4-AS1在PDAC中表达上调，且与预后不良呈正相关。DDIT4-AS1沉默抑制了茎的生长，并增强了对吉西他滨的敏感性。机制上，DDIT4-AS1通过阻止SMG5和PP2A与UPF1的结合而促进UPF1的磷酸化，从而降低DDIT4 mRNA的稳定性，激活mTOR通路。此外，在PDX衍生模型中抑制DDIT4-AS1增强了GEM对PDAC的抗肿瘤作用。机制总结示意图图片来源: https://doi-org.libproxy1.nus.edu.sg/10.1186/s12943-022-01647-0 总之，在PDAC细胞中，DDIT4-AS1被扩增、过表达并被ALKBH5和HUR稳定。DDIT4-AS1是一种癌基因，可显著促进PDAC的茎化并抑制对GEM的化疗敏感性。DDIT4-AS1与UPF1在物理上相互作用，覆盖SMG5和PP2A的结合部位，促进UPF1的磷酸化、DDIT4 mRNA的降解和mTOR途径的激活。在以PDX为基础的模型中，DDIT4-AS1 shRNA与GEM联合治疗显著增加了PDAC的抗肿瘤活性。DDIT4AS1的发现为PDAC癌症的发生提供了洞察力，并可能促进癌症筛查和治疗的精确方法的开发。（生物谷 Bioon.com）参考文献 Yi Zhang et al. The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway. Mol Cancer. 2022 Sep 2;21(1):174. doi: 10.1186/s12943-022-01647-0.