IKKbeta:Bi-Functional Regulator of Hepatocyte Proliferation

IKKbeta：肝细胞增殖的双功能调节剂

• 批准号: 7261546
• 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/7261546
• 关键词: Adult; Animals; Apoptosis; Appendix; 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; Rate; Reporting; Role; Standards of Weights and Measures; 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（由适用提供）：该提案的长期目标是针对理解肝脏再生和肝癌发生的机制。原癌基因细胞周期蛋白D1是一种主要的细胞周期蛋白，是正常成年肝细胞增殖所必需的。已经确定了许多收敛的细胞内途径，这些途径调节肝细胞中的细胞周期蛋白D1表达，但没有报道说IKK？IKK？激酶是激活转录因子NF-KB的激活以及预防肝细胞凋亡是由细胞控制介导的，而不是由循环的TNFA介导的。新的研究表明，在70％的部分肝术后，小鼠肝脏再生的开始速度更快，二乙基硝胺引起的肝细胞癌癌（HCC）的发病率较高，而携带靶向肝细胞特异性IKK的小鼠的小鼠较高。相比之下，成年小鼠肝脏再生被钝化，HCC的入口在​​整个肝脏中携带细胞IKKB缺失（包括其造血细胞成分）的小鼠中减弱。可用的证据进一步表明，在这种正常肝脏再生的小鼠模型中（响应70％的部分肝切开术）和化学肝癌发生，正常的肝细胞（而不是肝干样细胞）是补偿性增殖和HCC的前体。这是增加肝细胞增殖概率的生长调节系统的变化，这可能会使这种肝细胞对生长因子和致癌性转化更加敏感。因此，由于它们与化学肝癌发生的关系，该提案将重点放在正常肝细胞中与IKK？相关的肝细胞生长改变上。具体而言，观察结果表明，IKK？是成年肝细胞增殖的双功能调节剂：直接在肝细胞内；并且，间接地在非核肝细胞内部。这种观察结果暗示了肿瘤抑制和肿瘤启动子在肝细胞和非核肝细胞IKK耳中的作用。细胞和分子生物学，小鼠遗传学以及源自正常和基因敲除小鼠特定菌株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。彼此之间，三个具体目标将检验以下假设：1] IKK？是成人肝细胞增殖的“被动”负调节剂。 2] IKK？在非核肝细胞中需要提供刺激成年肝细胞增殖的生长因子； 3]肝细胞IKKI2，通过增加JNK1和/或减少延长C-Jun表达的JNK2表达，在生长刺激的肝细胞中的缺失设施早熟的S期进入，增强AP-1的激活并刺激Cyclin D1的早期发作。肝细胞Ikk g和JNK2的共同调节表达均可促进肝细胞增殖，并增加肝细胞对致癌作用的敏感性。