Splicing variant of Cdc42 interacting protein-4 disrupts beta-catenin-mediated cell-cell adhesion: expression and function in renal cell carcinoma.

We have identified an alternative splicing variant in the Cdc42-interacting protein 4 (CIP4) gene in patients with renal cell carcinoma (RCC); almost 50% of the RCCs examined showed an aberrant splicing event in reverse transcription-PCR and the insertion of 19 nucleotides derived from intron9 based on a sequence analysis. This variant (CIP4-V) encodes a premature stop codon, resulting in the loss of a tyrosine phosphorylation site, the Cdc42 binding domain, and the SH3 domain. In this report, we show that overexpression of CIP4-V causes the formation of ubiquitinated aggresomes and a loss of cell-cell adhesion. We determined that CIP4-V increased the beta-catenin tyrosine phosphorylation levels that mediate Fer/Fyn tyrosine kinases and induced beta-catenin mistrafficking from cell membrane to cytoplasmic aggresome. These results indicate that CIP4 is critical for beta-catenin-mediated cell-cell adhesion and may be an important aspect of its functional contribution to RCC, especially with regard to metastasis and invasiveness.

Methylenetetrahydrofolate reductase polymorphism, alcohol intake, and risks of colon and rectal cancers in Korea.

Several, but not all, studies have reported that a variant genotype of the polymorphism (C677T) of 5,10-methylenetetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, is associated with a decreased risk of colorectal cancer. A case-control study was conducted to investigate the association of MTHFR polymorphism and heavy alcohol intake to colon and rectal cancer in Korean. Cases were a consecutive series of patients with histologically confirmed, incident colorectal cancer who were admitted to two university hospitals in Seoul, Korea between 1998 and 2000, and controls were selected at the same hospitals. A total of 243 cases (colon 111, rectum 132) and 225 controls were enrolled. While the genotype of MTHFR was not associated with the overall risk of colorectal cancer, increased colon cancer risk was found to be associated with the CT and TT genotypes combined (multivariate odds ratio [OR] 2.01, 95% confidence interval [CI] 1.14-3.53) compared with the wild type. The risk of rectal cancer was found to be, though statistically non-significant, lower in those with the CT and TT genotypes combined (multivariate OR 0.67, 95% CI: 0.43-1.07). Those consuming two or more drinks per day (30 g+/day) had nearly twice the colorectal cancer risk (multivariate OR 1.94, 95% CI 1.03-3.68) of light or non-drinkers (<5 g/day). The present study did not find a reduced risk of colorectal or rectal cancer among those with a variant genotype of the MTHFR polymorphism, but observed rather an increased risk of colon cancer, suggesting that the effects of the MTHFR genotype may differ in populations with different levels of folate intake.

Changes in the expression of leukocyte adhesion molecules throughout the acute phase of myocardial infarction.

Since increased leukocytes within days after the onset of acute myocardial infarction (AMI) may reflect an increased expression of the adhesion molecules necessary for effective endothelial transmigration, we evaluated the expression of adhesion molecules on leukocytes throughout the acute phase of MI. We measured the number of leukocytes and enzymes and the expression levels of CD11a, CD18, very-late-after-activation antigen-4 alpha, intracellular adhesion molecule-1 (ICAM-1) and L-selectin by flow cytometry before and after coronary intervention, and at 6, 12, 18, 48 and 72 hours of MI in 5 patients (AMI group). As controls, we measured these parameters in 5 patients who had been diagnosed with angina pectoris and underwent coronary intervention (AP group). In the AMI group the expression of monocyte CD11a was significantly increased after 6 hours, and CD18 and ICAM-1 expression were also significantly increased after 12 hours, whereas that of monocyte L-selectin was increased after 72 hours. In addition, the increased monocyte CD11a was accompanied by an increased number of monocytes and a greater expression of CD11a per cell in the AMI group. In conclusion, since CD11a and CD18 are expressed on the cell surface as a heterodimer and ICAM-1 is a ligand for CD11a/CD18, their increased expression may contribute to their adhesion to endothelium in ischemic regions and may lead to the formation of microaggregates.

Increased expression of monocyte CD11a and intracellular adhesion molecule-1 in patients with initial atherosclerotic coronary stenosis.

BACKGROUND: Cell adhesion molecules have been implicated in the adhesion of leukocytes to endothelial cells and therefore play a role in atherosclerosis, which is a frequent cause of morbidity and mortality in patients with coronary artery disease (CAD) or undergoing hemodialysis (HD). The levels of expression of leukocyte adhesion molecules were evaluated in patients with CAD or HD. METHODS AND RESULTS: The expression of leukocyte (ie, neutrophil, monocyte and lymphocyte) surface CD11a, CD18, intracellular adhesion molecule-1 (ICAM-1), very late antigen-4 alpha (VLA-4 alpha) and L-selectin was investigated by flow cytometry in 20 patients who were initially diagnosed with CAD (CAD group), 15 patients with coronary re-stenosed vessels (RESTE group), 20 undergoing HD (HD group) and 20 without CAD (CONT group). Monocyte surface expression of both CD11a and ICAM-1 in the CAD group was significantly higher than in the CONT group. Interestingly, when 15 patients with RESTE were analyzed, they showed monocyte CD11a and ICAM-1 expression levels comparable to those in the CONT group. On the other hand, there were no significant differences in the expression of CD11a, CD18, L-selectin or VLA-4 alpha between the HD group and CONT group, but monocyte L-selectin was increased in the CAD group compared with the CONT group. CONCLUSIONS: Because CD11a and CD18 are expressed on the cell surface as a heterodimer and ICAM-1 is a ligand for CD11a/CD18, this increased expression of CD11a and ICAM-1 may affect the development of initial atherosclerotic coronary stenosis, but not re-stenosis.

Relation of plasma folate and methylenetetrahydrofolate reductase C677T polymorphism to colorectal adenomas.

BACKGROUND: Folate intake may be related to decreased risk of colorectal cancer and adenomas. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate metabolism. We examined the relation between plasma folate status and colorectal adenomas with reference to effect modification by the genetic polymorphism (C677T) of MTHFR. METHODS: Study subjects were middle-aged Japanese men: 177 cases of colorectal adenomas and 192 controls with normal total colonoscopy. Statistical adjustment was made for hospital, rank in the Self Defense Forces, alcohol use, smoking, and body mass index. RESULTS: Plasma folate levels were slightly lower in adenoma cases than in controls. Adjusted odds ratio (OR) for high (>5.50 ng/ml) versus low plasma folate levels was 0.72 (95% CI: 0.46-1.14). As compared with subjects with the CC or CT genotype having low plasma folate levels, those with the TT genotype showed a decreased risk of colorectal adenomas when they had high levels of plasma folate (adjusted OR = 0.58, 95% CI: 0.21-1.61), and an increased risk when they had low folate levels (adjusted OR = 2.13, 95% CI: 0.82-5.54). There was no clear relation between plasma folate and colorectal adenomas among those with the CC or CT genotype. CONCLUSIONS: The findings suggest an interaction between folate and the MTHFR genotype on colorectal adenomas.

Adenosine activates aromatic L-amino acid decarboxylase activity in the kidney and increases dopamine.

Renal sodium handling is important for regulating BP, and renal dopamine and adenosine play an important role in renal sodium handling, however the interaction of these hormones in the kidney was not clarified. In in vivo experiments, adenosine significantly increased water and sodium excretion by 50% compared with vehicle when infused into the left renal artery, accompanied by an increase in urinary dopamine excretion in the left kidney. Neither water-sodium excretion nor dopamine excretion changed in the vehicle-infused kidney. Aromatic L-amino acid decarboxylase activity in the left kidney was significantly higher than that in the noninfused right kidney. The increase in water-sodium excretion induced by adenosine was significantly inhibited by SCH23390, a selective D1 receptor antagonist. In in vitro experiments, porcine renal proximal tubular cells were incubated with 250 microM L-dopa and N(6)-cyclohexyladenosine, an adenosine type 1 receptor agonist, after treatment with adenosine deaminase. N(6)-cyclohexyladenosine significantly increased dopamine formation at a concentration of 10(-9) to 10(-7) M, and this was completely inhibited by 1,3-dipropyl-8-cyclopentylxanthin, an adenosine A1 antagonist. These results show that renal dopamine synthesis is stimulated by adenosine through the activation of aromatic L-amino acid decarboxylase and suggest that adenosine leads to an increase in renal dopamine and natriuresis.