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The Mechanism and Therapeutic Potential of Targeting the Ninjurin Pathway for Tumors Carrying Wild-Type p53

靶向 Ninjurin 通路治疗携带野生型 p53 的肿瘤的机制和治疗潜力

基本信息

批准号：
10650436
负责人：
Xinbin Chen
金额：
$ 43.15万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650436
关键词：
Amino Acid Sequence Apoptosis Biological Biology Breast Cancer Cell Cell Adhesion Molecules Cell Aging Cell Cycle Arrest Cell Death Cell Migration Inhibition function Cessation of life Chronic Complex DNA Damage Data Databases Development Embryo Exposure to Extracellular Domain Family Feedback Fibroblasts Genes Genome Growth Health Human Hydrophobicity Immune response Inflammasome Inflammation Inflammatory Inflammatory Response Invaded MCF7 cell Malignant Neoplasms Mus Mutation N-terminal Neoplasm Metastasis Nerve Regeneration Neurons Pathologic Processes Pathway interactions Peptides Pilot Projects Play Predisposition Proteins Publishing Regulation Repression Role Schwann Cells Signal Transduction Spinal Ganglia Stress TP53 gene Testing The Cancer Genome Atlas Therapeutic Therapeutic Agents Transmembrane Domain Tumor Promotion Tumor Suppression Up-Regulation alpha helix angiogenesis cancer type cell growth cell motility drug development extracellular mRNA Translation migration neoplastic cell nerve injury novel novel anticancer drug overexpression systemic inflammatory response therapeutic target transcription factor tumor tumor progression tumorigenesis

项目摘要

Project Summary/Abstract The tumor suppressor p53 is often referred to as the “guardian of the genome”. Mutations of the p53 gene occur in ~50% of human cancer and loss of p53 function is known to play a central role in tumor progression and metastasis. Upon exposure to a stress signal, such as DNA damage, p53 transcription factor is activated and then induces an array of pro-survival and pro-death genes. Due to its potent role in tumor suppression, p53 is an attractive target for the development of new anticancer drugs. Nerve injury-induced protein 1 (Ninjurin1, NINJ1) and NINJ2 constitute the Ninjurin family of cell adhesion molecules and have been implicated in various pathological processes such as immune response. However, the role of NINJ1 and NINJ2 in tumorigenesis is unclear. We showed previously that NINJ1 is a target of p53 and in turn represses p53 mRNA translation. Thus, NINJ1 and p53 forms a negative feedback loop. Notably, our pilot study showed that NINJ1 and NINJ2 interact with each other through their N-terminal extracellular domains. We also found that like NINJ1, NINJ2 forms a negative regulatory loop with p53. To determine the biological significance of the NINJ1-NINJ2-p53 loop, we showed that: (1) loss of NINJ1 or NINJ2 inhibits cell migration and formation of tumor spheres and colonies in breast cancer cells and promote cellular senescence in mouse embryonic fibroblasts in a p53- dependent manner; (2) mice deficient in Ninj1 or Ninj2 are prone to chronic inflammation, which is likely due to enhanced pyroptosis through wild-type p53-dependent activation of NLRP3 inflammasome; (3) two small peptides, called Pep-1A and Pep-2A derived from N-terminal alpha helix domain of NINJ1 and NINJ2 protein were able to disrupt the formation of NINJ1-NINJ2 complex and elicit growth suppression. These observations prompt us to hypothesize that both NINJ1 and NINJ2 play a critical role in tumorigenesis through the p53 pathway. To test this, we will determine: (1) the feedback regulatory loops between NINJ1 and NINJ2 and between p53 and the Ninjurin family; (2) the biological significance of the NINJ1-NINJ2-p53 loop in tumor suppression; (3) whether the Ninj1- Ninj2-p53 loop can be targeted to kill tumor cells carrying wild-type p53.

项目总结/文摘