Mutated in colorectal cancer (MCC ) was originally identified as a candidate gene for familial adenomatous polyposis (FAP) but further study identified adenomatous polyposis coli (APC) as responsible for FAP and the physiologic/pathologic roles of MCC remained poorly understood. Recently, MCC promoter methylation was discovered as a frequent early event in a distinct subset of precursor lesions and colorectal cancer (CRC) associated with the serrated CRC pathway. Here we provide the first evidence of the biological significance of MCC loss in CRC and the molecular pathways involved. We show MCC expression is dramatically decreased in many CRC cell lines and the distinct subset of sporadic CRC characterized by the CpG island methylator phenotype and BRAF V600E mutation due to promoter methylation as reported previously. Importantly, we find MCC interacts with b-catenin and that reexpression of MCC in CRC cells specifically inhibits Wnt signaling, b-catenin/T-cell factor/lymphoid-enhancer factor-dependent transcription and cellular proliferation even in the presence of oncogenic mutant APC. We also show that MCC is localized in the nucleus and identify two functional nuclear localization signals. Taken together, MCC is a nuclear, b-catenininteracting protein that can act as a potential tumor suppressor in the serrated CRC pathway by inhibiting Wnt/b-catenin signal transduction.
Breast cancer metastasis suppressor 1 (BRMS1) functions as a metastasis suppressor gene in breast cancer and melanoma cell lines, but the mechanism of BRMS1 suppression remains unclear. We determined that BRMS1 expression was inversely correlated with that of urokinase-type plasminogen activator (uPA), a prometastatic gene that is regulated at least in part by nuclear factor-KB (NF-KB). To further investigate the role of NF-KB in BRMS1-regulated gene expression, we examined NF-KB binding activity and found an inverse correlation between BRMS1 expression and NF-KB binding activity in MDA-MB-231 breast cancer and C8161.9 melanoma cells stably expressing BRMS1. In contrast, BRMS1 expression had no effect on activation of the activator protein-1 transcription factor. Further, we showed that suppression of both constitutive and tumor necrosis factor-A-induced NF-KB activation by BRMS1 may be due to inhibition of IKBA phosphorylation and degradation. To examine the relationship between BRMS1 and uPA expression in primary breast tumors, we screened a breast cancer dot blot array of normalized cDNA from 50 breast tumors and corresponding normal breast tissues. There was a significant reduction in BRMS1 mRNA expression in breast tumors compared with matched normal breast tissues (paired t test, P < < < < < 0.0001) and a general inverse correlation with uPA gene expression (P < < < < < 0.01). These results suggest that at least one of the underlying mechanisms of BRMS1-dependent suppression of tumor metastasis includes inhibition of NF-KB activity and subsequent suppression of uPA expression in breast cancer and melanoma cells. (Cancer Res 2005; 65(9): 3586-95)
In order to address an age-dependent alteration in the concentration of β-amyloid polypeptides (Aβs) within the central nervous system and its probable predisposition to amyloidgenesis in Alzheimer’s disease (AD), we measured two species of soluble Aβs, Aβ40 and Aβ42, in cerebrospinal fluids (CSF) from randomly selected Japanese control subjects at various ages (n = 33) and then compared these data with those of probable Japanese AD patients (n = 23). CSF concentrations of Aβ40 and Aβ42 peptides were age-dependent (ANOVA, Bonferroni’s multiple comparison; p < 0.01 and p < 0.05, respectively) and were lower in the infant than in adults. From mid-20, the Aβ40 concentrations were decreasing while Aβ42 were rather stable. Aβs in CSF from AD patients (n = 23), whose ε4 allele frequency of the apolipoprotein E gene was higher than in controls (n = 83, p < 0.03), were not statistically different from those of age-matched controls (n = 13). A linear relationship was detected between the Aβ40 concentration and the Mini-Mental State Examination score (p < 0.05). The ratio of the Aβ42 to the Aβ40 level measured in the AD CSF samples was approximately 38% decreased compared to age-matched controls (p < 0.05). These data suggest that the physiological metabolism of soluble Aβs in the brain is regulated in an age-dependent manner, and that the ratio of Aβ42 to Aβ40 level in the CSF would be a useful marker for monitoring progression of AD.
1, INTRODUCTION
MetallotlCxxins(MTs), low molecular-weight, heavy-metal-binding, cysteinc-rich cyrosolic proteins were first isolated from horse kidney and characterized by Vallee and co-workers [1,2]. Since then, MTs have been found in a number of species [3]. The function of MT has been debated ever since its discovery. A role in metal metabolism or detoxification is strongly suggested by the ability of MTs to bind to and be induced by heavy metal ions [4], Kelley et al, reported that overexpression of MT represents one mechanism of resistance to anticancer agents [S]. In recent years, immunohistochemical methods have provided new interesting information on MT intracellular distribution in the hepatocytes. MT is mainly localized in the nuclei of both fetal and neonatal rat hepatocytes, and the intranuclear 10calization of MT decreases with age [6], In human liver, the localization of MT is very similar to that in rat hepatocytes [7]. However, the biological significance of the presence of MT in nuclei is not yet clearly understood.We observed that MT suppressed the formation of gastric ulcer in rats [S]. Moreover, immuno-
To gain insight of the underlying mechanisms of astroglial response to Alzheimer’s disease (AD), the level of glial fibrillary acidic protein (GFAP) in cerebrospinal fluid (CSF) from controls and AD subjects were immunochemically determined, and the correlation between that level and dementia severity of AD patients was evaluated. Means and SD of CSF levels of GFAP for the young control group (from 1 to 25 years, mean ± SD 14.2 ± 5.0, n = 13) adult control (from 26 to 55 years, 41.6 ± 10.1, n = 9) and senescent control (older than 56 years, 65.4 ± 8.0, n = 8) were 2.96 ± 1.04, 2.80 ± 1.46 and 3.99 ± 1.55 ng/ml, respectively, and the CSF level of GFAP was not dependent on age (ANOVA, p = 0.17). While that of the AD patient group (n = 27, 70.8 ± 8.0 years) was 8.96 ± 7.80 ng/ml, significantly higher than that of both the all-control (3.19 ± 1.39 ng/ml, t test, p < 0.001) and age-matched senescent (3.99 ± 1.55 ng/ml, t test, p < 0.005) control groups. The receiver-operator characteristic (ROC) curve revealed that the GFAP concentration at 5 ng/ml in CSF could serve as a cutoff value. The CSF level of GFAP in the moderately to severely demented patients (MMSE ≤ 17, 13.2 ± 9.10 ng/ml, n = 9) was approximately by two-fold higher than that of the mildly to moderately demented patients (MMSE ≧ 18, 6.85 ± 5.76 ng/ml, n = 18; ANOVA, p < 0.05). These findings together with our previous report on an increase in the CSF level of apolipoprotein E suggest that degeneration and stimulation of astrocytes takes place concurrently in the AD brain.
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