RESUMO
Older adults in the nursing home are at high risk for polypharmacy. This article provides a background of older adults in nursing homes and reviews key steps to address polypharmacy.
Assuntos
Casas de Saúde , Polimedicação , Idoso , Humanos , Prescrição InadequadaRESUMO
Neuroleptic malignant syndrome (NMS) is an obstetric emergency. Management of acute psychosis in a pregnant patient remains complicated with limited therapeutic options due to teratogenic effects. We report a case in which a patient's antipsychotic regimen during a viable pregnancy subsequently led to NMS, and discuss our chosen management for treating NMS.
RESUMO
TRC8 encodes an E3-ubiquitin ligase disrupted in a family with hereditary renal cell carcinoma (RCC). We previously reported that Drosophila Trc8 (DTrc8) overexpression inhibits growth and that human and fly proteins interact with with the COP9 signalosome (CSN) subunit JAB1/CSN5. However, further mechanistic evidence linking DTrc8 growth suppression to CSN5 was lacking. Here, we show that haploinsufficiency of CSN5, or a T100I point mutation (CSN5(3)), relieved growth suppression by DTrc8, whereas CSN5(1) (E160V) and CSN5(2) (G147D) mutations had no effect. The strength of yeast two-hybrid interactions between DTrc8 and CSN5 were in complete agreement with the observed phenotypes. DTrc8 overexpression resulted in elevated levels of CSN5 and CSN7, but had no effect on NEDD8-modified Cul-1. In contrast to CSN5, heterozygosity for CSN4null had no effect on the DTrc8 phenotype. We also looked for genetic interactions between DTrc8 and other MPN domain proteins in the CSN and 26S proteasome lid. CSN6 haploinsufficiency restored growth, whereas reduction of proteasome subunits RPN8 or RPN11 had no effect. DTrc8 expression increased the level of digitonin-extractable CSN complex, consistent with elevated levels of CSN5 and 7. Our genetic results confirm that DTrc8-induced growth suppression is CSN5 (and CSN6) dependent. While there was no obvious influence on CSN deneddylation activity, the increase in CSN subunits and holocomplex suggests that TRC8 modulates signalosome levels or compartmentalization.
Assuntos
Carcinoma de Células Renais/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Proteínas de Drosophila/biossíntese , Proteínas de Drosophila/genética , Neoplasias Renais/genética , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Metaloendopeptidases/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas Adaptadoras de Transdução de Sinal , Sequência de Aminoácidos , Animais , Complexo do Signalossomo COP9 , Carcinoma de Células Renais/fisiopatologia , Proliferação de Células , Drosophila , Regulação da Expressão Gênica , Humanos , Neoplasias Renais/fisiopatologia , Dados de Sequência Molecular , Fenótipo , Mutação Puntual , Transdução de Sinais , Regulação para Cima , LevedurasRESUMO
VHL is part of an SCF related E3-ubiquitin ligase complex with 'gatekeeper' function in renal carcinoma. However, no mutations have been identified in VHL interacting proteins in wild type VHL tumors. We previously reported that the TRC8 gene was interrupted by a t(3;8) translocation in a family with hereditary renal and non-medullary thyroid cancer. TRC8 encodes a multi-membrane spanning protein containing a RING-H2 finger with in vitro ubiquitin ligase activity. We isolated the Drosophila homologue, DTrc8, and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either DTrc8 or DVhl resulted in an identical ventral midline defect. Direct interaction between DTrc8 and DVhl was confirmed by GST-pulldown and co-immunoprecipitation experiments. CSN-5/JAB1 is a component of the COP9 signalosome, recently shown to regulate SCF function. We found that DTrc8 physically interacts with CSN-5 and that human JAB1 localization is dependent on VHL mutant status. Lastly, overexpression of DTrc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Thus, VHL, TRC8, and JAB1 appear to be linked both physically and functionally and all three may participate in the development of kidney cancer.
Assuntos
Proteínas de Drosophila/fisiologia , Ligases/fisiologia , Proteínas de Membrana/fisiologia , Transdução de Sinais , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Células 3T3 , Animais , Complexo do Signalossomo COP9 , Células COS , Carcinoma de Células Renais/genética , Linhagem Celular , Proteínas de Ligação a DNA/análise , Drosophila/química , Drosophila/embriologia , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Retículo Endoplasmático/química , Feminino , Genes Supressores de Tumor , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Renais/genética , Ligases/genética , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Mutação , Peptídeo Hidrolases , Estrutura Terciária de Proteína , Receptores de Superfície Celular , Fatores de Transcrição/análise , Proteína Supressora de Tumor Von Hippel-Lindau , Asas de Animais/embriologiaRESUMO
TRC8/RNF139 encodes an endoplasmic reticulum-resident E3 ubiquitin ligase that inhibits growth in a RING- and ubiquitylation-dependent manner. TRC8 also contains a predicted sterol-sensing domain. Here, we report that TRC8 protein levels are sterol responsive and that it binds and stimulates ubiquitylation of the endoplasmic reticulum anchor protein INSIG. Induction of TRC8 destabilized the precursor forms of the transcription factors SREBP-1 and SREBP-2. Loss of SREBP precursors was proteasome dependent, required a functional RING domain, occurred without generating processed nuclear forms, and suppressed SREBP target genes. TRC8 knockdown had opposite effects in sterol-deprived cells. In Drosophila, growth inhibition by DTrc8 was genetically suppressed by loss of specific Mprlp, Padlp N-terminal domain-containing proteins found in the COP9 signalosome and eIF3. DTrc8 genetically and physically interacted with two eIF3 subunits: eIF3f and eIF3h. Coimmunoprecipitation experiments confirmed these interactions in mammalian cells, and TRC8 overexpression suppressed polysome profiles. Moreover, high-molecular weight ubiquitylated proteins were observed in eIF3 immunoprecipitations from TRC8-overexpressing cells. Thus, TRC8 function may provide a regulatory link between the lipid and protein biosynthetic pathways.