Plk3, A New Player In The Hypoxia Regulatory Networ.

Plk3，缺氧调节网络的新玩家。

• 批准号: 8794432
• 负责人: WEI DAI
• 金额: $ 33.2万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794432
• 关键词: Ablation; Affect; Alleles; Animal Model; Antineoplastic Agents; Biochemical; Cancer Biology; Cell Death; Coupled; Cytokine-Inducible Kinase; Defect; Development; Ectopic Expression; Elderly; Embryo; Environmental Carcinogens; Exposure to; Fibroblasts; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Growth Factor; Health; Heterozygote; Human; Hypoxia; In Vitro; Knock-in Mouse; Knockout Mice; Knowledge; Laboratories; MAP Kinase Gene; Malignant Neoplasms; Mediating; Metals; Molecular; Mus; Neoplasm Metastasis; Nickel; Nuclear; Nuclear Export; Organ; Oxygen; PDPK1 gene; PLK3 gene; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Polo-Box Domain; Predisposition; Prognostic Factor; Proto-Oncogene Proteins c-akt; Regulation; Reporting; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Somatotropin; System; Testing; Treatment Failure; Tumor Angiogenesis; Vascularization; base; biological adaptation to stress; cancer therapy; cell growth; drug development; human PLK1 protein; hypoxia inducible factor 1; in vivo; mimetics; mouse Cre recombinase; mutant; neoplastic cell; nutrition; overexpression; response; toxicant; tumor; tumorigenesis

DESCRIPTION (provided by applicant): HIF-1 controls the transcription of many genes that are involved in key aspects of cancer biology. Overexpression of HIF-11, an inducible subunit of HIF-1 in response to hypoxia, is a prognostic factor in many cancers. The major signaling axis mediated by PI3K, PDK1, and Akt (also referred as protein kinase B) plays a significant role in the regulation of HIF-11 expression. Both GSK32 and MAPKs are also known to directly phosphorylate HIF-11, thereby affecting its stability and/or nuclear localization. To understand the regulatory network that suppresses tumor development and tumor angiogenesis, we have recently identified HIF-11 as a new in vitro substrate of Polo-like kinase 3 (Plk3). Plk3 strongly phosphorylates HIF-11 on serines 576 and 657 in vitro, two residues that lie in the oxygen-dependent degradation domain and near the nuclear export signal, respectively. By studying primary isogenic murine embryonic fibroblasts (MEFs), we have shown that PLK3-/- MEFs are hyper-sensitive to the induction of HIF-11 under hypoxia or treated with nickel, a hypoxia mimetic. Compared with that of wild- type MEFs, PLK3-/- MEFs contain a high level of Akt1/PKB activities, which is tightly associated with the inhibitory phosphorylation of GSK32. Consistent with the potential role of Plk3 in regulating the hypoxia signaling network, PLK3-/- mice develop tumors in various organs at an advanced age and PLK3-/- tumors are large in size and highly vascularized, suggesting active tumor angiogenesis. On the basis of these observations regarding physical and functional interactions between Plk3 and HIF-11, we hypothesize that Plk3 negatively regulates the hypoxia regulatory network and HIF-11-dependent tumor angiogenesis. To test the validity of this hypothesis, we will (i) study functional interaction between Plk3 and known signaling molecules, including GSK32 and MAPKs that phosphorylate HIF-11, and identify additional Plk3 target(s) upstream of Akt1, (ii) determine whether PLK3-/- mice are prone to tumorigenesis under hypoxia, and (iii) investigate whether mice harboring Plk3 phosphorylation-resistant mutant alleles of HIF-11 are more susceptible to tumorigenesis after nickel exposure. The combined in vitro and in vivo studies will greatly facilitate the elucidation of a new mechanism by which HIF-11 is regulated by Plk3 during hypoxic responses or after exposure to environmental carcinogens such as nickel compounds. A detailed understanding of the molecular regulation of HIF-11 will add significantly to the existing knowledge of tumor angiogenesis and tumor cell resistance to anti-cancer therapies.

描述（由申请人提供）：HIF-1控制癌症生物学关键方面的许多基因的转录。 HIF-11的过表达是HIF-1的诱导亚基对缺氧，是许多癌症的预后因素。由PI3K，PDK1和AKT介导的主要信号轴（也称为蛋白激酶B）在HIF-11表达的调节中起重要作用。 GSK32和MAPK也已知直接磷酸化HIF-11，从而影响其稳定性和/或核定位。为了了解抑制肿瘤发育和肿瘤血管生成的调节网络，我们最近将HIF-11确定为新的Polo样激酶3（PLK3）的新体外底物。 PLK3在体外强烈磷酸化HIF-11上的HIF-11，分别位于氧气依赖性降解域和核输出信号附近的两个残基。通过研究原发性等生鼠胚胎成纤维细胞（MEF），我们已经表明PLK3 - / - MEF对缺氧在缺氧下诱导HIF-11或用镍（镍（Mimimetic）治疗）过度敏感。与野生型MEF相比，PLK3 - / - MEF包含高水平的AKT1/PKB活性，这与GSK32的抑制性磷酸化密切相关。与PLK3在调节低氧信号网络中的潜在作用一致，PLK3 - / - 小鼠在高龄时发生了各种器官的肿瘤，PLK3 - / - 肿瘤的大小较大，并且高度血管化，表明活性肿瘤血管生成。根据这些观察结果，关于PLK3和HIF-11之间的物理和功能相互作用，我们假设PLK3负调节缺氧调节网络和HIF-111依赖性肿瘤血管生成。为了检验该假设的有效性，我们将（i）研究PLK3与已知信号分子之间的功能相互作用，包括磷酸化HIF-111的GSK32和MAPK，并确定AKT1上游的其他PLK3靶标，（ii）确定PLK3 - / - 小鼠是否在PLK3 - / - / - 小鼠中是否占据了象征性的繁殖力低下。 HIF-11的抗磷酸化 - 耐耐药性突变等位基因更容易受到镍暴露后的肿瘤发生。体外和体内研究的合并将极大地促进一种新机制的阐明，该机制在低氧反应期间或暴露于环境致癌物（如镍化合物）期间受到HIF-11的调节。对HIF-11的分子调节的详细理解将显着增加对肿瘤血管生成和抗肿瘤细胞对抗癌疗法的耐药性的知识。