RESUMO
Yes-associated protein 1 (YAP1) is a transcriptional co-activator downstream of Hippo pathway. The pathway exerts crucial roles in organogenesis and its dysregulation is associated with the spreading of different cancer types. YAP1 gene encodes for multiple protein isoforms, whose specific functions are not well defined. We demonstrate the splicing of isoform-specific mRNAs is controlled in a stage- and tissue-specific fashion. We designed expression vectors encoding for the most-represented isoforms of YAP1 with either one or two WW domains and studied their specific signaling activities in YAP1 knock-out cell lines. YAP1 isoforms display both common and unique functions and activate distinct transcriptional programs, as the result of their unique protein interactomes. By generating TEAD-based transcriptional reporter cell lines, we demonstrate individual YAP1 isoforms display unique effects on cell proliferation and differentiation. Finally, we illustrate the complexity of the regulation of Hippo-YAP1 effector in physiological and in pathological conditions of the heart.
Assuntos
Proteínas de Ciclo Celular , Isoformas de RNA , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Sinalização YAPAssuntos
Terapia Antirretroviral de Alta Atividade , Antivirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Hepatite B/tratamento farmacológico , Hepatite C/tratamento farmacológico , Infecções por HIV/complicações , Hepatite B/complicações , Hepatite C/complicações , Humanos , Interferons/uso terapêutico , Ribavirina/uso terapêuticoRESUMO
The aim of this paper is to establish whether there are cytochemical or ultrastructural alterations in the hepatocytes of patients with primary biliary cirrhosis (PBC) at stages I and II compared with the biopsies from individuals with normal liver. Cytochemical technique with ATP as substrate, transmission electron microscopy (TEM) and freeze fracture were used for the studies. In the normal liver biopsies the ultrastructural cytochemical localization of the enzymatic activity was clearly shown in the bile canaliculi. In the PBC biopsies, the enzymatic activity is increased in the bile canaliculi and is also present in the lateral membranes of the hepatocyte. TEM of the lateral surface of the hepatocyte in normal livers showed a smooth surface without microvilli but in PBC livers a large number of microvilli were seen in the lateral membranes. The Golgi apparatus in these patients was localized not only near the canaliculi (normal livers) but also in front of the microvilli. Freeze-fracture showed normal features in the bile canaliculus junctions of the PBC patients. We suggest that the localization of the enzymatic reaction, microvilli and Golgi apparatus at the PBC hepatocyte lateral membranes may represent a compensatory mechanism for derivation of bile flow and other components from the hepatocyte to the intercellular space.
Assuntos
Cirrose Hepática Biliar/metabolismo , Fígado/metabolismo , Fígado/ultraestrutura , Trifosfato de Adenosina/metabolismo , Desmossomos/ultraestrutura , Técnica de Fratura por Congelamento , Humanos , Fígado/patologia , Microscopia EletrônicaRESUMO
The aim of this paper is to establish whether there are cytochemical or ultrastructural alterations in the hepatocytes of patients with primary biliary cirrhosis (PBC) at stages I and II compared with the biopsies from individuals with normal liver. Cytochemical technique with ATP as substrate, transmission electron microscopy (TEM) and freeze fracture were used for the studies. In the normal liver biopsies the ultrastructural cytochemical localization of the enzymatic activity was clearly shown in the bile canaliculi. In the PBC biopsies, the enzymatic activity is increased in the bile canaliculi and is also present in the lateral membranes of the hepatocyte. TEM of the lateral surface of the hepatocyte in normal livers showed a smooth surface without microvilli but in PBC livers a large number of microvilli were seen in the lateral membranes. The Golgi apparatus in these patients was localized not only near the canaliculi (normal livers) but also in front of the microvilli. Freeze-fracture showed normal features in the bile canaliculus junctions of the PBC patients. We suggest that the localization of the enzymatic reaction, microvilli and Golgi apparatus at the PBC hepatocyte lateral membranes may represent a compensatory mechanism for derivation of bile flow and other components from the hepatocyte to the intercellular space.(AU)
Assuntos
Humanos , Fígado/metabolismo , Fígado/ultraestrutura , Cirrose Hepática Biliar/metabolismo , Trifosfato de Adenosina/metabolismo , Desmossomos/ultraestrutura , Técnica de Fratura por Congelamento , Fígado/patologia , Microscopia EletrônicaRESUMO
The aim of this paper is to establish whether there are cytochemical or ultrastructural alterations in the hepatocytes of patients with primary biliary cirrhosis (PBC) at stages I and II compared with the biopsies from individuals with normal liver. Cytochemical technique with ATP as substrate, transmission electron microscopy (TEM) and freeze fracture were used for the studies. In the normal liver biopsies the ultrastructural cytochemical localization of the enzymatic activity was clearly shown in the bile canaliculi. In the PBC biopsies, the enzymatic activity is increased in the bile canaliculi and is also present in the lateral membranes of the hepatocyte. TEM of the lateral surface of the hepatocyte in normal livers showed a smooth surface without microvilli but in PBC livers a large number of microvilli were seen in the lateral membranes. The Golgi apparatus in these patients was localized not only near the canaliculi (normal livers) but also in front of the microvilli. Freeze-fracture showed normal features in the bile canaliculus junctions of the PBC patients. We suggest that the localization of the enzymatic reaction, microvilli and Golgi apparatus at the PBC hepatocyte lateral membranes may represent a compensatory mechanism for derivation of bile flow and other components from the hepatocyte to the intercellular space.
Assuntos
Humanos , Cirrose Hepática Biliar/metabolismo , Fígado/metabolismo , Fígado/ultraestrutura , Trifosfato de Adenosina , Desmossomos , Fígado/patologia , Técnica de Fratura por Congelamento , Microscopia EletrônicaRESUMO
The aim of this paper is to establish whether there are cytochemical or ultrastructural alterations in the hepatocytes of patients with primary biliary cirrhosis (PBC) at stages I and II compared with the biopsies from individuals with normal liver. Cytochemical technique with ATP as substrate, transmission electron microscopy (TEM) and freeze fracture were used for the studies. In the normal liver biopsies the ultrastructural cytochemical localization of the enzymatic activity was clearly shown in the bile canaliculi. In the PBC biopsies, the enzymatic activity is increased in the bile canaliculi and is also present in the lateral membranes of the hepatocyte. TEM of the lateral surface of the hepatocyte in normal livers showed a smooth surface without microvilli but in PBC livers a large number of microvilli were seen in the lateral membranes. The Golgi apparatus in these patients was localized not only near the canaliculi (normal livers) but also in front of the microvilli. Freeze-fracture showed normal features in the bile canaliculus junctions of the PBC patients. We suggest that the localization of the enzymatic reaction, microvilli and Golgi apparatus at the PBC hepatocyte lateral membranes may represent a compensatory mechanism for derivation of bile flow and other components from the hepatocyte to the intercellular space.
