Yutaka Nishii

Inhibition of Peroxisome Proliferator Signaling Pathways by Thyroid Hormone Receptor COMPETITIVE BINDING TO THE RESPONSE ELEMENT

Peroxisome proliferators (e.g. clofibric acid) and thyroid hormone play an important role in the metabolism of lipids. These effectors display their action through their own nuclear receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid hormone receptor (TR). PPAR and TR are ligand-dependent, DNA binding, trans-acting transcriptional factors belonging to the erbA-related nuclear receptor superfamily. The present study focused on the convergence of the effectors on the peroxisome proliferator response element (PPRE). Transcriptional activation induced by PPAR through a PPRE was significantly suppressed by cotransfection of TR in transient transfection assays. The inhibition, however, was not affected by adding 3,5,3′-triiodo-L-thyronine (T3). Furthermore, the inhibition was not observed in cells cotransfected with retinoic acid receptor or vitamin D3 receptor. The inhibitory action by TR was lost by introducing a mutation in the DNA binding domain of TR, indicating that competition for DNA binding is involved in the molecular basis of this functional interaction. Gel shift assays revealed that TRs, expressed in insect cells, specifically bound to the 32P-labeled PPRE as heterodimers with the retinoid X receptor (RXR). Both PPAR and TR bind to PPRE, although only PPAR mediates transcriptional activation via PPRE. TR·RXR heterodimers are potential competitors with PPAR·RXR for binding to PPREs. It is concluded that PPAR-mediated gene expression is negatively controlled by TR at the level of PPAR binding to PPRE. We report here the novel action of thyroid hormone receptor in controlling gene expression through PPREs.

Sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a kidney transplant recipient.

A case of sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a cadaver renal transplant recipient is reported in this article. The patient underwent a kidney transplant at the age of 43 and was treated with various immunosuppressive agents after surgery. Twelve months after the transplantation, multiple tumors were found in the liver, and the patient died 8 months later. Pathological examination at autopsy revealed renal cell carcinoma with a sarcomatoid component in the right native kidney and metastases to liver and bones. It is unusual for renal cell carcinoma to undergo sarcomatous transformation and to metastasize to the liver before reaching other organs. We speculate that immunosuppressants may have altered malignant cell proliferation, invasion, and the form of metastasis in this case.

Effects of 7-isopropoxy-3-phenyl-4H-1-benzopyran-4-one (ipriflavone) on serum levels of calcitonin and parathyroid hormone in patients with adult-onset diabetes

The effects of 1α-hydroxycholecalciferol [1α(OH)D3] and 7-isopropoxy-3-phenyl-4H-1-benzopyran-4-one [ipriflavone (IP)] on the serum concentrations of parathyroid hormone (PTH) and calcitonin (CTN) were studied in patients with adult-onset diabetes (NIDDM). A group of 122 NIDDM patients with unrestricted caloric intake were divided by random sampling into dietary (D) and non-dietary (ND) groups. Group D was placed on a calorie-restricted diet while group ND remained free of dietary restrictions. Two years after the groups were so divided, the groups were further divided by random sampling into 2 sub-groups (D1 and D2; ND1 and ND2). Groups D1 and ND1 received 1α(OH)D3 for 2 months, followed by combined IP/1α(OH)D3 administration for 6 months, and groups D2 and ND2 received a placebo in place of 1α(OH)D3. Serum PTH levels were higher and serum CTN levels were lower in group D than in group ND. Administration of 1α(OH)D3 to group D1 patients decreased serum PTH levels and increased serum calcium concentration, although serum CTN levels were not affected. Serum CTN levels were found to increase significantly (p<0.01), without changes in serum PTH concentrations, during the 6 months, combination treatment of 1α(OH)D3 and IP. IP also increased CTN levels in group ND2 and in patients in group D2 who had no prior 1α(OH)D3 treatment. IP did not, however, increase serum CTN levels significantly in patients whose serum PTH concentration was relatively high (500 pg/ml or more). These results suggest that IP is suitable for increasing serum CTN levels in NIDDM patients, and that its action is dependent on serum PTH levels.