Inhibitory PAS (Per/Arnt/Sim) domain protein (IPAS) is a dominant negative transcription factor that represses hypoxia-inducible factor 1 (HIF-1) activity. In this study, we show that IPAS also functions as a pro-apoptotic protein through binding to pro-survival Bcl-2 family members. In a previous paper, we reported that NF-jB-dependent IPAS induction by cobalt chloride repressed the hypoxic response in PC12 cells. We found that prolonged incubation under the same conditions caused apoptosis in PC12 cells. Repression of IPAS induction protected cells from apoptosis. Furthermore, knockdown of IPAS recovered cell viability. EGFP-IPAS protein was localized in both the nucleus and the cytoplasm, with a large fraction associated with mitochondria. Mitochondrial IPAS induced mitochondria depolarization and caspase-3 activation. Immunoprecipitation assays revealed that IPAS is associated with Bcl-x L , Bcl-w and Mcl-1. The association of IPAS with Bcl-x L was also observed in living cells by the FLIM-based FRET analysis, indicating direct binding between the two proteins. IPAS contributed to dysfunction of Bcl-x L by inhibiting the interaction of Bcl-x L with Bax. These results demonstrate that IPAS functions as a dual function protein involved in transcription repression and apoptosis.
Hypoxia-inducible factor 1 (HIF-1) is a master regulator for hypoxic activation of genes for angiogenesis, hormone synthesis, glycolysis and cell survival. In addition to hypoxic stimulus, various effectors and reagents were reported to affect HIF-1 activity. Here, we show that cyclic AMP (cAMP) down-regulates the HIF-1 activity in pheochromocytoma PC12 cells but not in Hep3B and HeLa cells. Hypoxia response element-dependent reporter activity was decreased by the addition of dibutyryl cAMP. Expression of protein kinase A (PKA) catalytic alpha-subunits repressed the HIF-1 activity. HIF-1alpha and HLF (HIF-2alpha or EPAS1) protein levels were decreased by the treatment with dibutyryl cAMP. Although CREB was served as a negative factor for the HIF-1 activity, it may not be a major PKA target in the cAMP-dependent HIF-alpha repression pathway. Induction of hypoxia responsive genes was suppressed by dibutyryl cAMP. Our results provide additional insight into a regulatory mechanism of hypoxic response.
An 85-year-old Japanese woman had noticed erythema on her vulvar region 3 years before. The erythema gradually increased in size and followed erosion and ulceration with pigmentation on the edge of the erythema. A skin biopsy from the pigmented area showed large round cells with ample cytoplasm, which formed nests or glandular structures. In the dermis there was mass formation of basophilic cells and peripheral cells in a palisade arrangement. The tumor cells in the epidermis showed positive immunoreactivity for carcinoembryonic antigen; on the other hand, the dermal tumor was negative. We diagnosed that the tumor in the epidermis was vulvar Paget’s disease, and the dermal tumor was a solid type of basal cell carcinoma. We speculate that the vulvar Paget’s disease preceded and then the basal cell carcinoma developed in the area of Paget’s disease. This is the first report in which basal cell carcinoma in the area of Paget’s disease was documented.
We report a rare case of squamous cell carcinoma developing from fistules of chronic perianal pyoderma in a 49-year-old Japanese man. He first noticed an abscess and nodule on his buttocks and perianal area 21 year previously (at the age of 28); the fistules formed later. These fistules were surgically removed, and an artificial anus was constructed 14 years ago (at the age of 35) in our hospital, when a histopathological examination revealed no malignant changes. However, he was recently admitted to our hospital with arterial bleeding from the ulcer of the buttock. On admission, the histological diagnosis of the ulcer was well differentiated squamous cell carcinoma. Wide local excision of the ulcer and scar tissue, including the sacrum, was performed. The defect was covered with a left latissimus dorsi flap and skin graft. He received radiation therapy after the operation. However, he died of cachexia and pneumonia. This case indicated that the CPP would better have been treated with wide excision before the development of SCC. Therefore, we recommend careful follow-up of patients affected by CPP and repeated biopsies of the lesion, particularly when the condition is severe, longstanding, and extensive. We discussed the term "CPP" and reviewed 22 cases of SCC arising in CPP reported in the Japanese literature.
We report two patients with chilblain lupus erythematosus of Hutchinson (CL) who responded to surgical treatment. One of them was a 72-year-old woman (case 1), and the other a 62-year-old man (case 2). We attempted to treat these patients by excising the lesions and subsequently performing full-thickness free skin grafting, using skin from the abdominal region. No recurrence was seen in the operated area 7 years (case 1) and 3 years (case 2) after surgery. However, lesions persisted in the areas not operated upon, and in the areas where lesions had not been adequately excised. These results suggest that surgical removal of local factors reduces the rash in these cases. In addition, both patients were serologically positive for the anti-Ro/SS-A antibody suggesting that local expression of the Ro/SS-A antigen may be involved in the pathogenesis of the skin lesions. To our knowledge, full thickness free skin grafting has not been used previously to treat CL-associated skin lesions, and is promising as a treatment for patients who do not respond to conventional means.
We report a case of pretibial myxedema with Graves' disease in an 18-year-old Japanese woman. The physical examination revealed waxy indurated plaques with prominent hair follicle openings and nonpitting edema disseminated on her lower legs. Histology from an edematous lesion revealed that the dermis was markedly thickened with abundant mucin, especially hyaluronic acid, and the collagen fibers in this portion were splitting up into fibrils. We also reviewed 112 cases of pretibial myxedema reported in the Japanese literature.
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