Role of promyelocytic leukemia (PML) protein in tumor suppression.
Role of promyelocytic leukemia (PML) protein in tumor suppression.
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DOI：
10.1084/jem.193.4.521
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发表时间：
2001-02-19
期刊：
影响因子：
--
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
--
作者：
Rego EM;Wang ZG;Peruzzi D;He LZ;Cordon-Cardo C;Pandolfi PP
在绝大多数急性早幼粒细胞白血病患者中，由于染色体易位，早幼粒细胞白血病基因与维甲酸受体α(RARα)基因融合，编码参与细胞凋亡调控的肿瘤抑制基因。PMLRARα癌蛋白被认为通过与核体异源二聚体和使核体非定域化而拮抗PML的功能。在APL中，这可能是通过降低正常PML等位基因的杂合性来实现的。为了确定PML在体内是否起到肿瘤抑制作用，以及非调控的程序性细胞死亡在白血病和上皮性肿瘤发病机制中的后果，我们分别将PML−/−小鼠与人组织蛋白酶G(HCG)-pMLRARα或乳腺肿瘤病毒/neu转基因小鼠(TM)进行杂交，建立了白血病和乳腺癌的模型。在PMLRARαTM中，随着PML剂量的逐渐减少，白血病的发病率显著增加，并加速了白血病的发病。相比之下，PML失活并不影响Neu诱导的肿瘤形成。在PMLRARαTM的造血细胞中，PML失活导致对分化药物如RA和维生素D3的反应减弱，而对促凋亡刺激具有显著的存活优势。这些结果表明：(A)PML通过使细胞对促凋亡和分化刺激产生抵抗而在体内发挥肿瘤抑制作用；(B)PML单倍体功能不全和PmLRARα对PML的功能损害是APL发病机制中的关键事件；以及(C)对程序性细胞死亡的异常控制在实体瘤和白血病的发病机制中起着不同的作用。
The promyelocytic leukemia (PML) gene encodes a putative tumor suppressor gene involved in the control of apoptosis, which is fused to the retinoic acid receptor α (RARα) gene in the vast majority of acute promyelocytic leukemia (APL) patients as a consequence of chromosomal translocations. The PMLRARα oncoprotein is thought to antagonize the function of PML through its ability to heterodimerize with and delocalize PML from the nuclear body. In APL, this may be facilitated by the reduction to heterozygosity of the normal PML allele. To determine whether PML acts as a tumor suppressor in vivo and what the consequences of deregulated programmed cell death in leukemia and epithelial cancer pathogenesis are, we crossed PML−/− mice with human cathepsin G (hCG)-PMLRARα or mammary tumor virus (MMTV)/neu transgenic mice (TM), models of leukemia and breast cancer, respectively. The progressive reduction of the dose of PML resulted in a dramatic increase in the incidence of leukemia, and in an acceleration of leukemia onset in PMLRARα TM. By contrast, PML inactivation did not affect neu-induced tumorigenesis. In hemopoietic cells from PMLRARα TM, PML inactivation resulted in impaired response to differentiating agents such as RA and vitamin D3 as well as in a marked survival advantage upon proapoptotic stimuli. These results demonstrate that: (a) PML acts in vivo as a tumor suppressor by rendering the cells resistant to proapoptotic and differentiating stimuli; (b) PML haploinsufficiency and the functional impairment of PML by PMLRARα are critical events in APL pathogenesis; and (c) aberrant control of programmed cell death plays a differential role in solid tumor and leukemia pathogenesis.
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BCL-2与临时细胞白血病视网膜酸受体α嵌合蛋白（PMLRARALALPHA）合作以阻断中性粒细胞分化并启动急性白血病。
DOI：
10.1084/jem.193.4.531
发表时间：
2001-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kogan SC;Brown DE;Shultz DB;Truong BT;Lallemand-Breitenbach V;Guillemin MC;Lagasse E;Weissman IL;Bishop JM
通讯作者：
Bishop JM
DOI：
10.1073/pnas.94.10.5302
发表时间：
1997-05-13
影响因子：
11.1
作者：
He, LZ;Tribioli, C;Pandolfi, PP
通讯作者：
Pandolfi, PP
影响因子：
30.8
作者：
Wang, ZG;Ruggero, D;Pandolfi, PP
通讯作者：
Pandolfi, PP
影响因子：
56.9
作者：
KING, CR;KRAUS, MH;AARONSON, SA
通讯作者：
AARONSON, SA
影响因子：
64.8
作者：
KLIEWER, SA;UMESONO, K;EVANS, RM
通讯作者：
EVANS, RM