Leukotriene Biosynthesis: Inflammation and Cancer

携带失活p53肿瘤抑制因子的细胞中基因组完整性的丧失在肿瘤学中具有严重后果。野生型p53 wt的失活可以源自其体细胞突变或源自其在胞质溶胶中的分离，在胞质溶胶中其作为转录因子被激活。 在以炎性乳腺癌和神经母细胞瘤为代表的侵袭性肿瘤中，或以腺瘤性息肉为代表的肿瘤前病变中，p53 wt的胞质分离不涉及其体细胞突变或其被病毒癌蛋白隔离。 因此，p53 wt的表观遗传失活必须涉及其他未知的参与者和过程。 我们将测试三个综合假设：1）与急性或慢性炎症相关的癌症风险升高部分源于p53 wt的化学损伤，该化学损伤扰乱了其构象并有利于其在细胞质中分离，细胞质是一种与其肿瘤抑制功能不相容的细胞区室。2)p53 wt被亲电子类二十烷酸或其他炎症的亲电子介质灭活将降低常规抗肿瘤剂的功效并使预后恶化。 肿瘤发生可能以不同的速率或通过不同的分子途径进行，这取决于p53 wt失活的性质（体细胞突变与表观遗传失活）。3)炎症的亲电脂质介体，以来源于脂氧合酶和环氧合酶催化生物合成途径的某些类花生酸为代表，通过以下方式促成这种表观遗传形式的p53失活：i）与p53 wt直接反应或ii）与控制p53构象和功能完整性的蛋白质间接反应。 我们的初步数据出现从我们的观察，代理独立的p53 wt可能是实验上无法区分的代理失活p53 wt，除非有人故意检查这两个，单独的可能性。 暴露于具有亲电子取代基的脂质的细胞在其胞质溶胶中积累构象紊乱的形式p53 wt，将其从其细胞核中排除，使其不能反式激活p53 wt应答基因，从而降低其对p53 wt依赖性细胞凋亡的易感性。 发现和表征p53 wt失活的新的表观遗传机制对于癌症的诊断、治疗和预后具有直接意义。 我们的相关发现，使细胞通过p53 wt-非依赖性途径传播凋亡的过程对癌症的药理学直接重要。 我们预计，我们的研究将确定一种与癌症风险升高相关的新分子过程，以及类花生酸在基因组稳定性调节中的新作用。

Loss of genomic integrity in cells harboring an inactive p53 tumor suppressor has grave consequences in oncology. Inactivation of wild type p53wt can originate from its somatic mutation or from its segregation in the cytosol, where it is inoperative as a transcription factor. Cytoplasmic segregation of p53wt in aggressive neoplasms, typified by inflammatory breast cancer and neuroblastoma, or in pre-neoplastic lesions, typified by adenomatous polyps does not involve its somatic mutation or its sequestration by viral oncoproteins. Thus, epigenetic inactivation of p53wt must involve other, unknown participants and processes. We will test three integrated hypotheses: 1) Elevated risks of cancers associated with acute or chronic inflammation originate, in part, from a chemical impairment of p53wt that deranges its conformation and favors its segregation in the cytosol, a cellular compartment that is incompatible with its tumor suppressor function. 2) Inactivation of p53wt by electrophilic eicosanoids, or other electrophilic mediators of inflammation, will diminish the efficacy of conventional anti- neoplastic agents and worsen prognosis. Oncogenesis may proceed at different rates or via different molecular pathways depending on the nature of p53wt inactivation (somatic mutation versus epigenetic inactivation). 3) Electrophilic lipid mediators of inflammation, typified by certain eicosanoids derived from the lipoxygenase and cyclooxygenase catalytic pathways of biosynthesis, contribute to this epigenetic form of p53 inactivation via: i) direct reaction with p53wt or ii) indirect reaction with proteins that govern the conformational and functional integrity of p53. Our preliminary data emerge from our observations that agents acting independently of p53wt may be experimentally indistinguishable from agents inactivating p53wt unless one deliberately examines these two, separate possibilities. Cells exposed to lipids with an electrophilic substituent accumulate a conformationally deranged form p53wt in their cytosol, exclude it from their nucleus, disable its transactivation of p53wt responsive genes, and thereby reduce their susceptibility to p53wt -dependent apoptosis. Discovery and characterization of a novel, epigenetic mechanism for the inactivation of p53wt is directly significant for diagnosis, treatment, and prognosis of cancer. Our related discovery of a process that enables cells to propagate apoptosis via p53wt- independent pathways is directly significant to the pharmacology of cancer. We anticipate that our investigations will identify a novel molecular process associated with elevated risks of cancer and a novel role for eicosanoids in the modulation of genomic stability.