Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF‐1α, a basic helix–loop–helix PAS transcription factor, acts as a master regulator of oxygen homeostasis by upregulating various genes under low oxygen tension. Although genetic studies have indicated the requirement of HIF‐1α for hypoxia‐induced growth arrest and activation of p21cip1, a key cyclin‐dependent kinase inhibitor controlling cell cycle checkpoint, the mechanism underlying p21cip1 activation has been elusive. Here we demonstrate that HIF‐1α, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21cip1. The HIF‐1α antagonism is mediated by displacing Myc binding from p21cip1 promoter. Neither HIF‐1α transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF‐1α. In keeping with its antagonism of Myc, HIF‐1α also downregulates Myc‐activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF‐1α pathway, which regulates a distinct group of Myc target genes in response to hypoxia.

A new member of the aquaporin (AQP) family has been identified from rat testis. This gene, referred as aquaporin 7 (AQP7), encodes a 269-amino acid protein that contained the conserved NPA motifs of MIP family proteins. AQP7 has the amino acid sequence homology with other aquaporins (ϳ30%), and it is highest with AQP3 (48%), suggesting that both AQP3 and AQP7 belong to a subfamily in the MIP family. Injection of AQP7-cRNA into Xenopus oocytes expressed a 26-kDa protein detected by immunoblotting. The expression of AQP7 in oocytes stimulated the osmotic water permeability by 10-fold which was not inhibited by 0.3 mM mercury chloride. The Arrhenius activation energy for the stimulated water permeability was low (2.1 kcal/mol). AQP7 also facilitated glycerol and urea transport by 5-and 9-fold, respectively. The activation energy for glycerol was also low (5.3 kcal/mol after the correction of the endogenous glycerol permeability of oocytes). Northern blot analysis revealed a 1.5-kilobase pair transcript expressed abundantly in testis. In situ hybridization of testis revealed the expression of AQP7 at late spermatids in seminiferous tubules. The immunohistochemistry of testis localized the AQP7 expression at late spermatids and at maturing sperms. AQP7 may play an important role in sperm function.Recent studies have identified several water channels (aquaporins) that belong to the MIP family (reviewed in Ref.

Purpose: Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8).Experimental Design: The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume. Results: Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% (P < 0.001) and 89% (P < 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% (P < 0.001) and 74% (P < 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and downregulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells. Conclusion: Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasingVEGF and IL-8 production directly through glucocorticoid receptor in vivo.

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The current stratification model may represent a useful tool for clinicians treating patients with ureteral obstruction due to advanced cancer.

It has already been demonstrated that the Notch signaling system is essential for gametogenesis in the adult germ line of Caenorhabditis elegans. However, the role of the Notch signaling system in mammalian spermatogenesis has not been well investigated. Recently, it has been revealed that this signaling system is expressed in the mammalian testis by showing coexpression of Jagged 2 and its receptor, Notch 1, is consistent with Notch 1 being a cognate receptor for Jagged 2 in the mammalian testis. Therefore, we investigated expressions of messenger RNAs of Notch 1 and Jagged 2 in the testicular tissues of developing Sprague-Dawley rats by reverse transcription-polymerase chain reaction and Northern blot analysis, expressions of their proteins in the testicular tissues of developing rats, fertile human controls and infertile human patients with maturation arrest by immunohistochemistry, and effects of antibodies to this system by culturing rat testicular tissues with these antibodies. Transcripts of Notch 1 and Jagged 2 in the rat testis were positive throughout the examined period; these intensities became higher at day 13 after birth, coincidence with the formation of spermatocytes, and peaked at day 19 after birth. Expressions of Notch 1 and Jagged 2 were recognized at first in the perinuclear regions of spermatocytes in the rat testis as a round structure at day 19 after birth and thereafter in further differentiated germ cells as meiosis proceeded. In the adult rat testis, positive staining was present as a round structure in spermatocytes, as a typical horseshoe-shaped structure in round spermatids, and as a covering structure spreading around the nucleus of elongated spermatids, but not in spermatozoa. Notch 1 was recognized in the vacuole of the Golgi complex of primary spermatocytes and the acrosome of elongated spermatids with electron microscopy. When rat testicular tissues were cultured with anti-Notch 1 or anti-Jagged 2 antibody, round and elongated spermatids decreased after 5 and 7 days of culture, respectively, and disappeared at around 9 and 12 days of culture, respectively, with shrinkage of the diameter of seminiferous tubules. Spermatocytes, however, increased after 11 days of culture. Expressions of both proteins have been detected in the testicular tissues of human fertile controls as in the rat testicular tissues. However, Notch 1 expression has not been detected in testicular tissues of 11 patients with maturation arrest, whereas Jagged 2 expression has been recognized in all of them. In conclusion, the results presented in this study offer the possibility that Notch 1/Jagged 2 signaling system plays an important role for male germ cells to differentiate or at least to survive in the rat testis and fails to express in the testis of spermatogenic maturation arrest patients.

Aim : To assess the feasibility of our portless endoscopic radical nephrectomy via a single minimum incision, which narrowly permitted extraction of the specimen in the initial 80 patients. Methods : Radical nephrectomy was carried out extraperitoneally in patients with T1-3aN0M0 renal tumors using an endoscope through a single minimum incision without trocar ports and gas. All the instruments used were reusable.Results : The average length of incision, operative time and estimated blood loss were 6.6 cm (range, 4-9 cm), 3. 1 h (range, 1.7-5.6 h) and 324 mL (range, 10-2288 mL), respectively. The complication rate was 2.5% (2/80); complications included injury of the pleura and hemorrhage from the vena cava, both of which were repaired by suture during operation. Transfusion was performed in three patients (3.8%). Average times to oral feeding and walking were both 1.4 days. Wound pain was minimal and analgesics were generally not required by the second postoperative day. In patients with larger incisions (7 cm or more), estimated blood loss increased (approximately 100 mL on average) and oral feeding resumed later (0.3 days on average), relative to patients with smaller incisions (6 cm or less). However, overall results were similar between the two patient groups. In patients with a large tumor (7 cm or greater), operative time did not increase and complications and transfusions were both avoided. Conclusion : Portless endoscopic radical nephrectomy via a single minimum incision is a safe, reproducible, cost-effective and minimally invasive treatment option for patients with T1-3aN0M0 renal tumors.

p63, a homologue of the p53 gene, is considered to be essential for the normal development of stratified epithelia including urothelium. To examine possible roles of p63 in urothelial tumorigenesis, p63 expression was systematically examined in normal urothelium, low-grade papillary noninvasive (LPN) urothelial tumours, and high-grade or invasive carcinomas, using either an isoformnonspecific or a DN-isoform-specific antibody. Expression profiles of p63 were also analysed in cultured cells. Immunoreactivity with the two antibodies was virtually identical in tissue samples examined. Basal and intermediate cell layers of normal urothelium showed intense nuclear p63 immunostaining. This normal staining pattern was preserved in a majority of LPN tumours, whereas it was frequently impaired in high-grade or muscle-invasive carcinomas. At the mRNA level, DNp63 expression predominated over TAp63, and amounts of DNp63 mRNA correlated with p63 immunoreactivity, confirming that DNp63 accounts for p63 expressed in urothelial tissues. In cultured cells, DNp63 was also expressed in low-grade tumour cells as well as normal urothelial cells, but undetectable in high-grade aggressive carcinoma cells. Interestingly, impaired DNp63 expression significantly associated with reduced b-catenin expression that was possibly related to progression of urothelial neoplasms. Thus, impaired DNp63 expression characterises aggressive phenotypes of urothelial neoplasms.