Sumoylation is tumor-suppressive and confers proliferative quiescence to hematopoietic progenitors in Drosophila melanogaster larvae
Sumoylation is tumor-suppressive and confers proliferative quiescence to hematopoietic progenitors in Drosophila melanogaster larvae
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DOI：
10.1242/bio.2011043
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发表时间：
2012-03-15
期刊：
影响因子：
2.4
通讯作者：
Govind, Shubha
中科院分区：
文献类型：
--
作者：
Kalamarz, Marta E.;Paddibhatla, Indira;Govind, Shubha
细胞周期的细胞内在调节和小生境的外在影响如何会聚以提供增殖静止、保护组织完整性并提供阻止干细胞产生肿瘤的途径是基因治疗和组织工程中的主要挑战。我们探讨这个问题，在果蝇的sumoylation缺陷突变体。在野生型三龄幼虫淋巴腺，一组造血干/祖细胞获得静止，多细胞生态位支持其未分化状态。然而，增殖性静止是如何灌输在这一人群还不清楚。我们发现，Ubc 9蛋白是核在这个群体。SUMO激活E1酶Aos 1/Uba 2、结合E2酶Ubc 9或E3 SUMO连接酶皮亚斯的缺失导致祖细胞不能静止;祖细胞变得增生、错误分化并发展成最终从背侧血管脱离的微肿瘤。值得注意的是，当Ubc 9（wt）在祖细胞群体中特异性提供时，Ubc 9突变体的发育不良和致死性被拯救，但当它在小生境或分化的皮质中提供时，则不是。虽然正常的祖细胞表达高水平的果蝇细胞周期蛋白依赖性激酶抑制剂p21同源物，Dacapo，相应的过度生长的突变群体表现出显着减少Dacapo。Dacapo或人p21在祖细胞中的强制表达使该群体缩小。在突变的祖细胞中，而不是在其他造血群体中，选择性表达任一蛋白质，限制过度生长，阻断肿瘤发生，并恢复器官的完整性。我们讨论了一个必不可少的和复杂的作用sumoylation在维护造血祖细胞状态的压力反应和正常发展的背景下的苍蝇。(C)2011年。出版社：The Company of Biologists Ltd
How cell-intrinsic regulation of the cell cycle and the extrinsic influence of the niche converge to provide proliferative quiescence, safeguard tissue integrity, and provide avenues to stop stem cells from giving rise to tumors is a major challenge in gene therapy and tissue engineering. We explore this question in sumoylation-deficient mutants of Drosophila. In wild type third instar larval lymph glands, a group of hematopoietic stem/progenitor cells acquires quiescence; a multicellular niche supports their undifferentiated state. However, how proliferative quiescence is instilled in this population is not understood. We show that Ubc9 protein is nuclear in this population. Loss of the SUMO-activating E1 enzyme, Aos1/Uba2, the conjugating E2 enzyme, Ubc9, or the E3 SUMO ligase, PIAS, results in a failure of progenitors to quiesce; progenitors become hyperplastic, misdifferentiate, and develop into microtumors that eventually detach from the dorsal vessel. Significantly, dysplasia and lethality of Ubc9 mutants are rescued when Ubc9(wt) is provided specifically in the progenitor populations, but not when it is provided in the niche or in the differentiated cortex. While normal progenitors express high levels of the Drosophila cyclin-dependent kinase inhibitor p21 homolog, Dacapo, the corresponding overgrown mutant population exhibits a marked reduction in Dacapo. Forced expression of either Dacapo or human p21 in progenitors shrinks this population. The selective expression of either protein in mutant progenitor cells, but not in other hematopoietic populations, limits overgrowth, blocks tumorogenesis, and restores organ integrity. We discuss an essential and complex role for sumoylation in preserving the hematopoietic progenitor states for stress response and in the context of normal development of the fly. (C) 2011. Published by The Company of Biologists Ltd.