Analysis of tumor supressor genes p16 and Rb in childhood acute lymphoblastic leukemia

儿童急性淋巴细胞白血病抑癌基因p16和Rb分析

• 批准号: 14570734
• 负责人: SUGITA Kanji
• 金额: $ 1.79万
• 依托单位: University of Yamanashi (2003)山梨医科大学 (2002)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570734/
• 关键词: Rb gene; p16 gene; Cell cycle; ALL

Progression of the cell cycle is cooperatively regulated by a series of cyclin and cyclin-dependent kinase (CDK) complexes which elicit phosphorylation of retinoblastoma protein (Rb) resulting in release of several RB-associated transcription factors such as the E2F family required for G1 to S phase progression. p16/INK4a negatively regulates this process as one of CDK inhibitors, and is regarded as a tumor suppressor because of its frequent inactivation in a wide variety of tumors. Unexpectedly, however, recent reports have revealed the association of an enhanced p16 expression with an unfavorable outcome in several malignancies including childhood ALL. Along with the process of our study characterizing p16 in childhood ALL, we found a B-precursor ALL cell line (KOPN-79) with nonrandom translocations expressing p16 at extremely high levels. To clarify mechanism(s) allowing this cell line to cell cycle progression, we examined key regulators in the p16/Rb pathway, and identify the structural abnormality of the Rb gene. The resultant Rb product was rearranged and truncated at the site within the pocket region, and showed the poor binding capacity to the E2F-1. Our findings might explain, at least in part, the primary cause for an unfavorable outcome of childhood ALL over-expressing p16.

细胞周期的进展由一系列细胞周期蛋白和细胞周期蛋白依赖性激酶（CDK）复合物协同调节，所述复合物引起视网膜母细胞瘤蛋白（Rb）的磷酸化，导致几种RB相关转录因子的释放，例如G1期至S期进展所需的E2 F家族。p16/INK 4a作为CDK抑制剂之一负调节这一过程，并因其在多种肿瘤中频繁失活而被认为是肿瘤抑制因子。然而，出乎意料的是，最近的报告显示，在包括儿童ALL在内的几种恶性肿瘤中，p16表达增强与不良结局相关。沿着我们对儿童ALL中p16特征的研究，我们发现了一个非随机易位的B-前体ALL细胞系（KOPN-79），该细胞系表达极高水平的p16。为了阐明该细胞系细胞周期进展的机制，我们检测了p16/Rb通路中的关键调节因子，并鉴定了Rb基因的结构异常。所得的Rb产物在口袋区域内的位点发生重排和截短，与E2 F-1的结合能力较差。我们的研究结果可能至少部分解释了儿童ALL过度表达p16的不利结果的主要原因。

项目成果

Inukai T, Furuuchi K, Sugita K, Uno K, Mishina M, Ooi A, Sasaki F: "β-catenin and single allele mutation of the APC gene responsible for and occurrence of hepatoblastoma in familial adenomatous polyposis. A case report and review of the literature."Oncol

Inukai T、Furuuchi K、Sugita K、Uno K、Mishina M、Ooi A、Sasaki F：“β-连环蛋白和 APC 基因的单一等位基因突变导致家族性腺瘤性息肉病中肝母细胞瘤的发生。病例报告和综述文献。”Oncol

Yamakawa N, Sugita K, et al.: "Ligand activation of PPAR gamma induced apoptosis of human leukemia cells by downregulating the c-myc gene expression via blockade of the Tcf-4"Cell Death and Differentiation. 9. 513-526 (2002)

Yamakawa N、Sugita K 等人：“PPAR γ 的配体激活通过阻断 Tcf-4 下调 c-myc 基因表达来诱导人类白血病细胞凋亡”细胞死亡和分化。

Kobayashi N, Agematsu K, Sugita K, Sako M, Nonoyama S, Yachie A, Kumaki S, Kumaki S, Tsuchiya S, Ochs HD, Sugita K, Fukushima Y, Komiyama A.: "Novel Artemis gene mutations of radiosensitive severe combined immunodeficiency in Japanese families."Hum.Genet.

Kobayashi N、Agematsu K、Sugita K、Sako M、Nonoyama S、Yachie A、Kumaki S、Kumaki S、Tsuchiya S、Ochs HD、Sugita K、Fukushima Y、Komiyama A.：“放射敏感性严重联合免疫缺陷的新型 Artemis 基因突变

Tsutsumi S, Taketani T, Nishimura K, Ge X, Taki T, Sugita K, Ishii E, Hanada R, Ohki M, Aburatani H, Hayashi Y.: "Two distinct gene expression signatures in pediatric acute lymphoblastic leukemia with MLL rearraements."Cancer Res. 15. 4882-4887 (2003)

Tsutsumi S、Taketani T、Nishimura K、Ge X、Taki T、Sugita K、Ishii E、Hanada R、Ohki M、Aburatani H、Hayashi Y.：“伴有 MLL 重排的儿童急性淋巴细胞白血病的两种不同基因表达特征。”

Kato H, Ohta S, Koshida S, Narita T, Taga T, Takeuchi Y, Sugita K.: "Expression of pericyte, mesangium and muscle markers in malignant rhabdoid tumor cell lines : differentiation induction using 5-azacytidine."Cancer Sci. 12. 1059-1065 (2003)

Kato H、Ohta S、Koshida S、Narita T、Taga T、Takeuchi Y、Sugita K.：“恶性横纹肌样肿瘤细胞系中周细胞、系膜和肌肉标记物的表达：使用 5-氮杂胞苷进行分化诱导。”癌症科学。