Distinct E2F-Mediated Transcriptional Mechanisms in Cell Proliferation, Endoreplication and Apoptosis

E2F and DP family proteins are evolutionally conserved transcription factors among higher eukaryotes. E2F and DP proteins typically form a heterodimeric complex, which controls cell proliferation by regulating expression of growth-related genes. In addition, E2F family proteins have roles in various cellular events that require the expression of context-specific genes. E2F proteins use distinct mechanisms to regulate context-specific genes in different circumstances. The primary goal of this chapter is to compare three distinct mechanisms of mammalian E2F-mediated transcriptional regulation that control cell proliferation, endoreplication and apoptosis. Briefly, E2F7 and E2F8 control endoreplication by suppressing the expression of their target genes. They do not require DP or pRb. In control of apoptosis, E2F1 regulates the expression of the tumor suppressor gene Arf by binding to a non-canonical E2F binding site, within the Arf promoter, in a DP-independent manner. Furthermore, we examine the functions of E2F and DP in Drosophila melanogaster (fruit fly) to identify those mechanisms of E2F-mediated transcriptional regulation that have been evolutionarily conserved. The detailed mechanisms of how E2F protein regulates the expression of context-specific target genes will be instrumental in understanding how a single family of transcription factor regulates diverse pleiotropic cellular processes in an organism

Functional Polymorphisms in the Promoter Regions of Matrix Metalloproteinase-2, -3, -7, -9 and TNF-alpha Genes, and the Risk of Colorectal Neoplasm in Japanese

Colorectal carcinogenesis involves environmental factors and genetic predispositions. Recent studies have suggested the associations between colorectal neoplasm and functional polymorphism of matrix metalloproteinases (MMPs) and cytokine genes. In this study, we analyzed polymorphisms of MMPs and tumor necrosis factor (TNF)-alpha genes, focusing on the susceptibility to colorectal neoplasm and the tumor progression. The subjects were 186 patients (95 men and 91 women) who underwent total colonoscopy, and were classified into cancer, adenoma and non-neoplasm (control) groups of 47, 72 and 67 patients, respectively. The polymorphisms at the MMP-2 ?1306C/T, MMP-3 ?1171 5A/6A, MMP-7 ?181A/G, MMP-9 ?1562C/T and TNF-alpha ?308G/A loci were analyzed. Regarding background factors, significant differences were found in the age, sex ratio and alcohol-drinking and cigarette-smoking histories in the adenoma and cancer groups, compared to those in the control group. On these factors-adjusted logistic regression analysis of polymorphisms and disease susceptibility, no significant difference was noted in the frequency of any polymorphism in the adenoma and cancer groups, compared to those in the control group. The analysis of the involvement of polymorphisms in tumor progression in the adenoma and cancer groups revealed that the odds ratio for the MMP-3 5A allele was significantly higher in the cancer group (2.74; 95% confidence interval = 1.11?6.74, P = 0.02). The polymorphisms of MMP genes and TNF-alpha genes were not associated with the susceptibility to colorectal neoplasm, but the involvement of the MMP-3 5A allele in the progression of adenoma to cancer was suggested

The Key Role of E2F in Tumor Suppression through Specific Regulation of Tumor Suppressor Genes in Response to Oncogenic Changes

E2F, the principal target of the tumor suppressor pRB, plays crucial roles in tumor suppression. Upon dysfunction of pRB, E2F activates tumor suppressor genes such as ARF, an upstream activator of the tumor suppressor p53, resulting in the induction of apoptosis and tumor suppression. The E2F activity that activates the tumor suppressor genes is detected only in cancer cells and not in normal growing cells. The E2F activity can drive selective suicide gene expression and induce apoptosis specifically in cancer cells. Thus, the E2F activity provides a beneficial tool to specifically target cancer cells in cancer treatment

Association of Functional Gene Polymorphisms of Interleukin-1β and Transforming Growth Factor-β1 with the Progression of Liver Fibrosis in Japanese Patients with Hepatitis C Virus-Related Chronic Liver Disease

Interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1RN) are key cytokines in an inflammatory response, and transforming growth factor β1 (TGF-β1) promotes hepatic fibrogenesis. The association of polymorphisms in the genes for these cytokines with liver fibrosis is controversial. The aim of this study was to examine the possible association of IL-1β, IL-1RN and TGF-β1 polymorphisms with the progression of liver fibrosis in the Japanese population using cross-sectional and longitudinal study designs. We examined 183 patients with hepatitis C virus (HCV)-related chronic liver disease (93 chronic hepatitis and 90 with cirrhosis). Some of the chronic hepatitis cases were divided into progressive fibrosis and non-progressive fibrosis. IL-1β ?31T/C, IL-1RN variable number of tandem repeats (VNTR) and TGF-β1 +869 T/C polymorphisms were analyzed using a polymerase-chain reaction-based assay. In the cross-sectional study, there were no significant differences in the genotype distributions of IL-1β, IL-1RN and TGF-β1 between chronic hepatitis and liver cirrhosis. No significant differences were found among Child-Pugh grades in cirrhosis patients. In the longitudinal study, there were no significant differences in the genotype distributions of IL-1β, IL-1RN and TGF-β1 between progressive fibrosis and non-progressive fibrosis. No significant differences in the speed at which liver fibrosis develop were found among the genotypes of IL-1β, IL-1RN and TGF-β1. In disagreement with other studies, the functional gene polymorphisms of IL-1β, IL-1RN and TGF-β1 were not associated with the progression of liver fibrosis in Japanese patients with HCV-related chronic liver disease

A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis

We generated a mouse line in which the src homology 2 domain–bearing protein tyrosine phosphatase (SHP)-2 binding site of gp130, tyrosine 759, was mutated to phenylalanine (gp130F759/F759). The gp130F759/F759 mice developed rheumatoid arthritis (RA)-like joint disease. The disease was accompanied by autoantibody production and accumulated memory/activated T cells and myeloid cells. Before the disease onset, the T cells were hyperresponsive and thymic selection and peripheral clonal deletion were impaired. The inhibitory effect of IL-6 on Fas ligand expression during activation-induced cell death (AICD) was augmented in gp130F759/F759 T cells in a manner dependent on the tyrosine residues of gp130 required for signal transducer and activator of transcription 3 activation. Finally, we showed that disease development was dependent on lymphocytes. These results provide evidence that a point mutation of a cytokine receptor has the potential to induce autoimmune disease

Diagnosis of biliary tract and ampullary carcinomas

Diagnostic methods for biliary tract carcinoma and the efficacy of these methods are discussed. Neither definite methods for early diagnosis nor specific markers are available in this disease. When this disease is suspected on the basis of clinical symptoms and risk factors, hemato-biochemical examination and abdominal ultrasonography are performed and, where appropriate, enhanced computed tomography (CT) and/or magnetic resonance cholangiopancreatography (MRCP) is carried out. Diagnoses of extrahepatic bile duct cancer and ampullary carcinoma are often made based on the presence of obstructive jaundice. Although rare, abdominal pain and pyrexia, as well as abnormal findings of the hepatobiliary system detected by hemato-biochemical examination, serve as a clue to making a diagnosis of these diseases. On the other hand, the early diagnosis of gallbladder cancer is scarcely possible on the basis of clinical symptoms, so when this cancer is found with the onset of abdominal pain and jaundice, it is already advanced at the time of detection, thus making a cure difficult. When gallbladder cancer is suspected, enhanced CT is carried out. Multidetector computed tomography (MDCT), in particular — one of the methods of enhanced CT — is useful for decision of surgical criteria, because MDCT shows findings such as localization and extension of the tumor, and the presence or absence of remote metastasis. Procedures such as magnetic resonance imaging, endoscopic ultrasonography, bile duct biopsy, and cholangioscopy should be carried out taking into account indications for these procedures in individual patients. However, direct biliary tract imaging is necessary for making a precise diagnosis of the horizontal extension of bile duct cancer