An 83-year-old man, who had undergone right radical nephrectomy tor renal cell Carcinoma about 7 years previously, experienced nielena and abdominal mass. Barium enema, c:olonoscopy, computed tomography, and arteriography showed a hypervascular mass on the transverse colon, and a partial transverse colectomy was performed. The postoperative histologic examination revealed that the tumor was a metastatic clear cell carcinoma.
Positive cofactor 4 (PC4), originally identified as a transcriptional coactivator, possesses the ability to suppress promoter-driven as well as nonspecific transcription via its DNA binding activity. Previous studies showed that the repressive activity of PC4 on promoterdriven transcription is alleviated by transcription factor TFIIH, possibly through one of its enzymatic activities. Using recombinant TFIIH, we have analyzed the role of TFIIH for alleviating PC4-mediated transcriptional repression and determined that the excision repair cross complementing (ERCC3) helicase activity of TFIIH is the enzymatic activity that alleviates PC4-mediated repression via -␥ bond hydrolysis of ATP. In addition, the alleviation does not require either ERCC2 helicase or cyclin-dependent kinase 7 kinase activity. We also show that, as complexed within TFIIH, the cyclindependent kinase 7 kinase does not possess the activity to phosphorylate PC4. Thus, TFIIH appears to protect promoters from PC4-mediated repression by relieving the topological constraint imposed by PC4 through the ERCC3 helicase activity rather than by reducing the repressive activity of PC4 via its phosphorylation. Positive cofactor 4 (PC4)1 was originally identified in the upstream-factor stimulatory activity that augments activatordependent transcription in vitro (1, 2). PC4 stimulates transcription in vitro with diverse kinds of activators, including VP16 (3, 4), thyroid hormone receptor (5), octamer transcription factor-1 (6), and BRCA-1 (7), presumably by facilitating assembly of the preinitiation complex through bridging between activators and the general transcriptional machinery (4,8). Studies on the interaction of PC4 with activators and TFIIA, as well as in vitro functional analyses, suggest that interaction between TFIIA and PC4 plays a pivotal role for facilitating the preinitiation complex (PIC) assembly (3,4). Further studies also demonstrated the importance of PC4 for transcriptional activation by AP-2 (9) and HIV transactivator Tat (10) in vivo. In addition, a yeast homologue of PC4, SUB1/TSP1 (11, 12), which is essential for viability in the presence of TFIIB mutations (12), was shown to function as a coactivator for GCN4 and HAP proteins. The N-terminal region of PC4 contains a serinerich portion termed the SEAC domain, which exhibits similarity to viral immediate-early proteins (3). Phosphorylation of the serine residues in the SEAC domain negatively regulates the coactivator activity of PC4 (3, 13) possibly by a conformational change.In addition to the role as coactivator, PC4 was subsequently shown to repress promoter-driven transcription as well as nonspecific transcription in vitro (14, 15). The analyses of PC4 mutants demonstrated that the repressive activity is a separate function from the coactivator activity (14); therefore, the repressive activity of PC4 may play an as yet unknown function in regulating transcription in vivo. In fact, the primary function of PC4 in vivo could possibly be to repress transcription rather than to enhanc...
Hypertonicity mediated by chloride upregulates the expression of the gamma-subunit of Na-K-ATPase in cultured cells derived from the murine inner medullary collecting duct (IMCD3; Capasso JM, Rivard CJ, Enomoto LM, and Berl T. Proc Natl Acad Sci USA 100: 6428-6433, 2003). The purpose of this study was to examine the cellular locations and the time course of gamma-subunit expression after long-term adaptation and acute hypertonic challenges induced with different salts. Cells were analyzed by confocal immunofluorescence and immunoelectron microscopy with antibodies against the COOH terminus of the Na-K-ATPase gamma-subunit or the gamma(b) splice variant. Cells grown in 300 mosmol/kgH(2)O showed no immunoreactivity for the gamma-subunit, whereas cells adapted to 600 or 900 mosmol/kgH(2)O demonstrated distinct reactivity located at the plasma membrane of all cells. IMCD3 cell cultures acutely challenged to 550 mosmol/kgH(2)O with sodium chloride or choline chloride showed incorporation of gamma into plasma membrane 12 h after osmotic challenge and distinct membrane staining in approximately 40% of the cells 48 h after osmotic shock. In contrast, challenging the IMCD3 cells to 550 mosmol/kgH(2)O by addition of sodium acetate did not result in expression of the gamma-subunit in the membranes of surviving cells after 48 h. The present results demonstrate that the Na-K-ATPase gamma-subunit becomes incorporated into the basolateral membrane of IMCD3 cells after both acute hyperosmotic challenge and hyperosmotic adaptation. We conclude that the gamma-subunit has an important role in the function of Na-K-ATPase to sustain the cellular cation balance over the plasma membrane in a hypertonic environment.
The gamma-subunit of Na-K-ATPase (FXYD2) and corticosteroid hormone-induced factor (CHIF; FXYD4) are considered pump regulators in kidney tubules. The aim of this study was to expand the information about their locations in the kidney medulla and to evaluate their importance for electrolyte excretion in an animal model. The cellular and subcellular locations and abundances of gamma and CHIF in the medulla of control and sodium-depleted rats were analyzed by immunofluorescence and immunoelectron microscopy and semiquantitative Western blotting. The results showed that antibodies against the gamma-subunit COOH terminus and splice variant gamma(a), but not splice variant gamma(b), labeled intercalated cells, but not principal cells, in the initial part of the inner medullary collecting duct (IMCD1). In subsequent segments (IMCD2 and IMCD3), all principal cells exhibited distinct basolateral labeling for both the gamma-subunit COOH terminus, splice variant gamma(a), and CHIF. Splice variant gamma(b) was abundant in the inner stripe of the outer medulla but absent in the inner medulla (IM). Double labeling by high-resolution immunoelectron microscopy showed close structural association between CHIF and the Na-K-ATPase alpha(1)-subunit in basolateral membranes. The present observations provide new information about the cellular and subcellular locations of gamma and CHIF in the renal medulla and show a new gamma variant in the IM. Extensive NaCl depletion did not induce significant changes in the locations or abundances of the gamma-subunit COOH terminus and CHIF in different kidney zones. We conclude that the unchanged levels of these two FXYD proteins suggest that they are not primary determinants for urine electrolyte composition during NaCl depletion.
Adrenomedullin increased renal nitric oxide, and suppressed tubular apoptosis, interstitial fibrosis and inflammatory cell infiltration in mice with unilateral ureteral obstruction. The renoprotective peptide adrenomedullin may be useful for that condition.
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