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鲁兵卫《自然》解析一种新肿瘤抑制机制

2007.9.08

来自国立新加坡大学生命科学系,贝德福德老年教育研究临床中心(Geriatric Research, Education and Clinical Center, grecc )的研究人员发现有丝分裂激酶Polo通过磷酸化Pon(Numb的接头蛋白)调控肿瘤抑制蛋白Numb的非对称定位,这表明在细胞周期与非对称蛋白定位之间存在一个直接的生化联系,同时也揭示了一个新颖的肿瘤抑制机制。这一研究成果公布在《Nature》杂志上。

文章的通讯作者是来自GRECC的鲁兵卫博士以及William Chia,前者早年毕业于复旦大学,于康奈尔大学获得博士学位。

原文检索:
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]

恶性肿瘤的发生是长期困扰生物学家和临床医学家的巨大难题,攻克恶性肿瘤这个堡垒更是我们在下一世纪面临的巨大挑战。对恶性肿瘤的认识来自于对肿瘤细胞表型的观察和对恶性肿瘤患者病程及其转归的了解。人们最早观察到的,最引人注目的异于正常细胞的肿瘤细胞表型是其极强的,似乎是无限的增殖能力,远远超过正常细胞。这种增殖能力使肿瘤细胞数目在很短时间内就能成倍增加,并在患者体内形成瘤块,这种增殖能力本身就使肿瘤细胞相对正常细胞具有压倒的优势。不过,各个肿瘤细胞的增殖能力并不相同。 

其次,肿瘤细胞往往比相应的正常细胞更幼稚,处于更原始的分化阶段。所以,随着肿瘤细胞的大量增殖,这种原始或幼稚细胞便大量积聚。第三,肿瘤细胞的寿命比正常细胞长。正常细胞都有一定的寿命,寿命终结时细胞会自行死亡而在体内被清除,但肿瘤细胞却发生不死化,不能自行衰老消亡。第四,肿瘤细胞不但在原发灶之处不断增殖形成团块,还很容易从团块脱落而迁徙到远处,再固定在远处增殖形成新的团块。而正常细胞与组织粘附很牢,除非衰老死亡,一般不会脱落而迁徙到远处。无疑,恶性肿瘤主要是由于细胞增殖,分化,衰老,死亡等方面行为的异常和失衡所致肿瘤细胞的克隆性生长造成的。

自我更新和分异之间的平衡是干细胞和癌症生物学的基础。果蝇神经干细胞通过非对称细胞分裂做到这一点,在非对称细胞分裂期间,影响自我更新和分异的因素被非均等地隔离。在这篇文章中研究人员发现,有丝分裂激酶Polo通过磷酸化Pon(Numb的接头蛋白)调控肿瘤抑制蛋白Numb的非对称定位。Polo通过调控Pon/Numb来起一个肿瘤抑制剂的作用。这些发现表明在细胞周期与非对称蛋白定位之间存在一个直接的生化联系,同时也揭示了一个新颖的肿瘤抑制机制。

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

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