Non-canonical roles of Mitotic Arrest Deficient 1 (Mad1) in tumor promotion

有丝分裂停滞缺陷 1 (Mad1) 在肿瘤促进中的非典型作用

• 批准号: 10608148
• 负责人: Beth A Weaver
• 金额: $ 46.05万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608148
• 关键词: Acceleration; Alleles; Binding; Biochemistry; Breast Cancer Model; C-terminal; CRISPR/Cas technology; Cancer Patient; Cancerous breast; Cause of Death; Cell Cycle; Cell Cycle Checkpoint; Cells; Cellular biology; Chromosomal Instability; Clinical Trials; Defect; Dependence; Diagnosis; Disease; ECM receptor; Fibronectins; Genes; Goals; Golgi Apparatus; ITGA5 gene; Immune system; Immunocompromised Host; Impairment; Integrin Inhibition; Integrins; Interphase; Light; Mad1 protein; Malignant Neoplasms; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Messenger RNA; Microscopy; Mitosis; Mitotic; Mitotic Activity; Mitotic Checkpoint; Modeling; Mus; Mutate; Neoplasm Metastasis; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Play; Primary Neoplasm; Prognosis; Proteins; Publishing; Role; Series; Signal Transduction; TP53 gene; Testing; Tetanus Helper Peptide; Tetracyclines; Tumor Promotion; Up-Regulation; Woman; Work; antagonist; cell motility; chromosome missegregation; experimental study; improved; inhibitor; innovation; malignant breast neoplasm; mouse model; mutant; new therapeutic target; novel; orthotopic breast cancer; overexpression; prevent; promoter; trafficking; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis

Breast cancer is the most commonly diagnosed malignancy in women worldwide. Mitotic Arrest Deficient 1 (Mad1) is commonly upregulated in breast cancer where it serves as a marker of poor prognosis, and upregulation of Mad1 is sufficient for tumorigenesis in orthotopic breast cancer models. Mad1 was identified and characterized for its function in mitosis, where it serves to prevent chromosome missegregation/chromosomal instability (CIN). CIN has been implicated in promoting both primary and metastatic tumors. However, Mad1 is expressed throughout interphase and we have recently shown that a non-canonical interphase function of Mad1 in destabilizing the p53 tumor suppressor is critical for Mad1 upregulation to promote orthotopic mammary tumor growth. Additionally, we identified a previously unrecognized pool of Mad1 that localizes to the Golgi apparatus. At the Golgi, Mad1 performs another non-canonical function in the maturation and secretion of newly synthesized α5 integrin, a critical metastasis promoter and marker of poor prognosis. Thus, Mad1 upregulation results in three tumor- and metastasis-promoting phenotypes: CIN, p53 destabilization and α5 integrin secretion. Aim 1 will determine which functions of Mad1 upregulation are necessary and sufficient for tumor promotion using separation of function mutants, competition experiments, specific inhibitors, and novel CRISPR/Cas9 edited mouse models. Aim 2 will define the mechanisms by which Mad1 functions in the secretion of newly synthesized α5 integrin, which will provide novel opportunities to inhibit α5 integrin activity in promoting metastasis. Together, the proposed experiments will identify the mechanistic basis of the tumor promoting activity of Mad1 and define the α5 integrin biosynthetic trafficking pathway, which will expand our fundamental understanding of breast cancer and reveal novel therapeutic targets.

乳腺癌是全球女性最常见的恶性肿瘤。有丝分裂停滞不足1 （MAD1）通常在乳腺癌中上调，它是预后不良的标志，并且 MAD1的上调足以用于原位乳腺癌模型中的肿瘤发生。 MAD1被识别为 其在有丝分裂中的功能的特征，它用于预防染色体错误分泌/染色体 不稳定（CIN）。 CIN已暗示促进原发性和转移性肿瘤。但是，Mad1是 在整个期间表达 在破坏p53肿瘤抑制器时，对于MAD1上调促进原位乳腺肿瘤至关重要 生长。此外，我们确定了先前未知的MAD1池，该池定位于高尔基体。 在Golgi，MAD1在新合成的成熟和分泌方面执行了另一个非规范功能 α5整合素，一种关键的转移启动子和预后不良的标志物。那是MAD1上调导致 三种肿瘤和转移的表型：CIN，p53破坏稳定和α5整联蛋白分泌。目标1 将确定哪些MAD1上调的功能是必要的，并且足以促进使用 编辑功能突变体，竞争实验，特定抑制剂和新型CRISPR/CAS9的分离 鼠标模型。 AIM 2将定义MAD1在新合成的分泌中起作用的机制 α5整合素将为抑制α5整合素活性在促进转移中的活性提供新的机会。一起， 提出的实验将确定MAD1肿瘤促进活性的机理基础并定义 α5整联蛋白生物合成运输途径将扩大我们对乳房的基本理解 癌症并揭示了新的治疗靶标。