IKKbeta:Bi-Functional Regulator of Hepatocyte Proliferation

IKKbeta：肝细胞增殖的双功能调节剂

• 批准号: 7624633
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7624633
• 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)：这项建议的长期目标是为了了解肝脏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。已发现许多调节肝细胞周期蛋白D1表达的汇聚性细胞内通路，但尚未见IKK在其中的报道。IKK是转录因子NF-KB激活所必需的，也是通过细胞结合而不是循环中的TNFa介导的防止肝细胞凋亡所必需的。新的研究表明，在70%的肝部分切除后，携带靶向肝细胞特异性ikk？缺失的小鼠的肝再生开始得更快，二乙基亚硝胺诱导的肝细胞癌(HCC)的发病率更高。相比之下，成年小鼠的肝脏再生迟钝，肝癌的发病率在整个肝脏中携带细胞IKKB缺失的小鼠中减少，包括其造血细胞成分。现有证据进一步表明，在这种正常肝再生(对70%的肝部分切除)和化学性肝癌形成的小鼠模型中，正常肝细胞--而不是肝干细胞--是代偿性增殖和肝细胞癌的前驱细胞。因此，增加肝细胞增殖几率的生长调节系统的变化很可能会使这些肝细胞对生长因子和致癌转化更加敏感。因此，鉴于它们与化学性肝癌发生的关系，本研究将集中于正常肝细胞中与IKK相关的肝细胞生长变化。具体地说，观察表明IKK？是成人肝细胞增殖的双功能调节器：直接在肝细胞内，间接在非实质肝细胞内。这些观察结果暗示了肝细胞和非实质肝细胞的抑癌和促癌作用。细胞和分子生物学的标准程序，小鼠遗传学，以及来自正常和基因敲除小鼠特定品系的组织和细胞的分析，将被用来在成人肝细胞中研究这些预测。因此，三个特定的目标将检验下列假设：1)IKK？是成人肝细胞增殖的“被动”负调控因子；2)IKK？在非实质肝细胞中是必需的，以提供刺激成年肝细胞增殖的生长因子；以及3)肝细胞IKKI2缺失通过增加JNK1和/或降低JNK2的表达，促进生长刺激肝细胞的早熟S相进入，从而延长c-jun的表达，增强AP-1的激活，并刺激细胞周期蛋白D1的提前表达。减弱肝细胞IKK和JNK2的共调控表达可能既促进了肝细胞的增殖，又增加了肝细胞癌变的易感性。