魯兵衛《自然》解析一種新腫瘤抑制機制

來自國立新加坡大學生命科學系，貝德福德老年教育研究臨床中心(Geriatric Research, Education and Clinical Center， grecc )的研究人員發現有絲分裂激酶Polo通過磷酸化Pon（Numb的接頭蛋白）調控腫瘤抑制蛋白Numb的非對稱定位，這表明在細胞周期與非對稱蛋白定位之間存在一個直接的生化聯系，同時也揭示了一個新穎的腫瘤抑制機制。這一研究成果公布在《Nature》雜志上。

文章的通訊作者是來自GRECC的魯兵衛博士以及William Chia，前者早年畢業于復旦大學，于康奈爾大學獲得博士學位。

原文檢索：
Nature 449, 96-100 (6 September 2007) |
doi:10.1038/nature06056; Received 28 May 2007; Accepted 28 June 2007
Polo inhibits progenitor self-renewal and regulates Numb asymmetry by phosphorylating Pon
[Abstract]

惡性腫瘤的發生是長期困擾生物學家和臨床醫學家的巨大難題，攻克惡性腫瘤這個堡壘更是我們在下一世紀面臨的巨大挑戰。對惡性腫瘤的認識來自于對腫瘤細胞表型的觀察和對惡性腫瘤患者病程及其轉歸的了解。人們最早觀察到的，最引人注目的異于正常細胞的腫瘤細胞表型是其極強的，似乎是無限的增殖能力，遠遠超過正常細胞。這種增殖能力使腫瘤細胞數目在很短時間內就能成倍增加，并在患者體內形成瘤塊，這種增殖能力本身就使腫瘤細胞相對正常細胞具有壓倒的優勢。不過，各個腫瘤細胞的增殖能力并不相同。　

其次，腫瘤細胞往往比相應的正常細胞更幼稚，處于更原始的分化階段。所以，隨著腫瘤細胞的大量增殖，這種原始或幼稚細胞便大量積聚。第三，腫瘤細胞的壽命比正常細胞長。正常細胞都有一定的壽命，壽命終結時細胞會自行死亡而在體內被清除，但腫瘤細胞卻發生不死化，不能自行衰老消亡。第四，腫瘤細胞不但在原發灶之處不斷增殖形成團塊，還很容易從團塊脫落而遷徙到遠處，再固定在遠處增殖形成新的團塊。而正常細胞與組織粘附很牢，除非衰老死亡，一般不會脫落而遷徙到遠處。無疑，惡性腫瘤主要是由于細胞增殖，分化，衰老，死亡等方面行為的異常和失衡所致腫瘤細胞的克隆性生長造成的。

自我更新和分異之間的平衡是干細胞和癌癥生物學的基礎。果蠅神經干細胞通過非對稱細胞分裂做到這一點，在非對稱細胞分裂期間，影響自我更新和分異的因素被非均等地隔離。在這篇文章中研究人員發現，有絲分裂激酶Polo通過磷酸化Pon（Numb的接頭蛋白）調控腫瘤抑制蛋白Numb的非對稱定位。Polo通過調控Pon/Numb來起一個腫瘤抑制劑的作用。這些發現表明在細胞周期與非對稱蛋白定位之間存在一個直接的生化聯系，同時也揭示了一個新穎的腫瘤抑制機制。

附：
Bingwei Lu

Email: bingwei@stanford.edu
Academic Appointments AppointmentOrganizationAssistant ProfessorPathologyGraduate & Fellowship Program

Honors & AwardsTitleOrganizationDate(s)

McKnight Scholar AwardThe McKnight Endowment Fund for Neurosciences2002
Career Scientist AwardMonique Weill-Caulier Trust2002
Speaker's Fund for Biomedical Research AwardNew York Academy of Sciences2002
Young Investigator AwardThe Arnold and mabel Beckman Foundation2002
Research FellowThe Alfred P. Sloan Foundation2002

Professional EducationDegreeAwarding InstitutionField of StudyYear of Graduation
Ph.D.Cornell University Genetics and Development 1995
B.S.Fudan UniversityGenetics 1987

Research Interests

Our laboratory is interested in understanding how the diverse neuronal cell types are generated and maintained in the nervous system. We are taking a combined molecular, cellular, genetic, and genomic approach in the model organism Drosophila to address these questions. To study how neuronal diversity is generated, we focus on investigating the mechanisms of asymmetric division of neural stem cell that produces daughter cells with different developmental potentials. To study how neurons are properly maintained after they are integrated into neural networks, we are creating neurodegenerative phenotypes in Drosophila similar to that observed in Alzheimer’s and Parkinson’s diseases in humans. We are employing the power of fly genetics to identify genetic modifiers that can suppress or enhance these disease phenotypes. Given the unanticipated high level conservation of signaling pathways, regulatory mechanisms, and physiological processes between flies and mammals, our research promises to provide insights into fundamental mechanisms that control the generation and maintenance of neuronal diversity in humans.

Publications
Zhang Y, Guo H, Kwan H, Wang JW, Kosek J, Lu B "PAR-1 Kinase Phosphorylates Dlg and Regulates Its Postsynaptic Targeting at the Drosophila Neuromuscular Junction." Neuron 2007; 53: 2: 201-15
Wang, J-W., Imai Y., Lu, B. "Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1" The Journal of Neuroscience 2007; 27: 3: 574-581 
Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, Wang JW, Yang L, Beal MF, Vogel H, Lu B "Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin." Proc Natl Acad Sci U S A 2006; More ?
Yang Y, Gehrke S, Haque ME, Imai Y, Kosek J, Yang L, Beal MF, Nishimura I, Wakamatsu K, Ito S, Takahashi R, Lu B "Inactivation of Drosophila DJ-1 leads to impairments of oxidative stress response and phosphatidylinositol 3-kinase/Akt signaling." Proc Natl Acad Sci U S A 2005;
Nishimura I, Yang Y, Lu B "PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila." Cell 2004; 116: 5: 671-82