IKKbeta:Bi-Functional Regulator of Hepatocyte Proliferation

IKKbeta：肝细胞增殖的双功能调节剂

• 批准号: 7807061
• 负责人: HYAM L LEFFERT
• 金额: $ 29.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-31 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7807061
• 关键词: Adult; Animals; Apoptosis; Attenuated; Binding; Blood; Carcinogens; Catalytic Domain; Cell Cycle; Cell Cycle Proteins; Cell membrane; Cells; Chemical Dynamics; Chemicals; Complex; Controlled Study; Cyclin D1; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cyclins; Diethylnitrosamine; Equilibrium; Extrahepatic; Goals; Growth; Growth Factor; Hematopoietic; Hepatocarcinogenesis; Hepatocyte; Hepatocyte Growth Factor; Incidence; Injury; Investigation; Knockout Mice; Laboratories; Lead; Liver; Liver Regeneration; Liver Stem Cell; MAPK8 gene; MAPK9 gene; Malignant Neoplasms; Mediating; Metabolism; Modeling; Molecular and Cellular Biology; Mus; Non-Malignant; Nuclear; Nuclear Receptors; Partial Hepatectomy; Pathway interactions; Phase; Phosphotransferases; Predisposition; Prevention; Primary carcinoma of the liver cells; Probability; Procedures; Proliferating; Protein Kinase; Proteins; Proto-Oncogenes; Publishing; Reporting; Role; Stimulus; System; Testing; Tissues; Transcription Factor AP-1; Tumor Promoters; Tumor Suppressor Proteins; Uncertainty; Viral; carcinogenesis; early onset; genetic analysis; in vitro Model; in vivo; insight; intrahepatic; liver cell proliferation; mouse model; novel; response; transcription factor

DESCRIPTION (provided by applicant): The long-term goals of this proposal are directed towards understanding mechanisms of liver regeneration and hepatocarcinogenesis. Proto-oncogene cyclin D1 is a major cell-cycle protein that is necessary for normal adult hepatocyte proliferation. Many convergent intracellular pathways have been identified that regulate cyclin D1 expression in hepatocytes, but there are no reports that IKK¿ is among them. IKK¿ kinase is required for activation of transcription factor NF-KB and for the prevention of hepatocyte apoptosis mediated by cell-bound but not by circulating TNFa. New investigations have revealed that following 70% partial hepatectomy, mouse liver regeneration starts faster and the diethylnitrosamine- induced incidence of hepatocellular carcinoma (HCC) is higher in mice carrying targeted hepatocyte-specific IKK¿ deletions. In contrast, adult mouse liver regeneration is blunted and the incidence of HCC is attenuated in mice carrying cellular IKKB deletions throughout the liver including its hematopoietic cellular components. Available evidence further suggests that, in this mouse model of normal liver regeneration (in response to 70% partial hepatectomy) and chemical hepatocarcinogenesis, normal hepatocytes - not liver stem cells -- are precursors of compensatory proliferation and HCC. Thus, changes in growth regulatory systems that increase the probabilities of hepatocyte proliferation may well make such hepatocytes more sensitive to growth factors and to carcinogenic transformation. Therefore, owing to their relationship to chemical hepatocarcinogenesis, this proposal will focus on hepatocyte growth alterations related to IKK¿ in normal hepatocytes. Specifically, the observations suggest that IKK¿ is a bi-functional regulator of adult hepatocyte proliferation: directly inside hepatocytes; and, indirectly inside non-parenchymal liver cells. Such observations implicate tumor suppressor and tumor promoter roles for hepatocyte and non-parenchymal liver cell IKK¿. Standard procedures of cellular and molecular biology, mouse genetics, and analyses of tissues and cells derived from specific strains of normal and knockout mice, will be used to investigate these predictions in adult liver cells. Accordingly, three specific aims will test the following hypotheses: 1] IKK¿ is a 'passive' negative regulator of adult hepatocyte proliferation; 2] IKK¿ is required in nonparenchymal liver cells for provision of growth factors that stimulate adult hepatocyte proliferation; and, 3] Hepatocyte IKKI2, deletion facilitates precocious S-phase entry in growth-stimulated hepatocytes by increasing JNK1 and/or reducing JNK2 expression which prolong c-JUN expression, enhance AP-1 activation and stimulate early onset expression of cyclin D1. Attenuated co-regulated expression of hepatocyte IKK¿ and JNK2 may both facilitate hepatocyte proliferation and increase the susceptibility of hepatocytes to carcinogenesis.

描述（由申请人提供）：该提案的长期目标是了解肝再生和肝癌发生的机制。原癌基因细胞周期蛋白 D1 是正常成人肝细胞增殖所必需的主要细胞周期蛋白。已确定调节肝细胞中细胞周期蛋白 D1 表达的途径，但尚无 IKK 的报道IKK 就是其中之一。激酶是激活转录因子 NF-KB 以及预防由细胞结合而非循环 TNFa 介导的肝细胞凋亡所必需的。新的研究表明，70% 部分肝切除术后，小鼠肝脏再生开始更快，并且二乙基亚硝胺诱导。携带靶向肝细胞特异性 IKK 的小鼠肝细胞癌 (HCC) 的发病率较高¿相比之下，在整个肝脏（包括其造血细胞成分）中携带细胞 IKKB 缺失的成年小鼠肝脏再生减弱，并且 HCC 的发病率降低。现有证据进一步表明，在这种正常肝脏再生的小鼠模型中。到 70% 部分肝切除术）和化学性肝癌发生，正常肝细胞（而非肝干细胞）是代偿性增殖和 HCC 的前体，因此，生长调节系统的变化会增加肝癌的发生。肝细胞增殖的可能性很可能使此类肝细胞对生长因子和致癌转化更加敏感，因此，由于它们与化学性肝癌发生的关系，本提案将重点关注与 IKK 相关的肝细胞生长改变。具体而言，观察结果表明 IKK¿是成人肝细胞增殖的双功能调节剂：直接在肝细胞内；以及间接在非实质肝细胞内。这些观察结果表明 IKK 对肝细胞和非实质肝细胞具有抑癌和促癌作用。细胞和分子生物学、小鼠遗传学以及对来自正常和基因敲除小鼠的特定品系的组织和细胞的分析的标准程序将用于研究成年肝细胞中的这些预测。因此，三个具体目标将测试以下假设。 : 1] IKK¿是成人肝细胞增殖的“被动”负调节因子 2] IKK¿非实质肝细胞需要提供刺激成体肝细胞增殖的生长因子；并且，3] 肝细胞 IKKI2，缺失可通过增加 JNK1 和/或减少 JNK2 表达来促进生长刺激的肝细胞过早进入 S 期，从而延长 c-JUN表达，增强 AP-1 激活并刺激细胞周期蛋白 D1 的早期表达，减弱肝细胞 IKK 的共同调节表达。 JNK2可能既促进肝细胞增殖，又增加肝细胞癌变的易感性。