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Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function.

Abstract
We report unexpected nongenomic functions of signal transducer and activator of transcription (STAT) 5 species in the cytoplasm aimed at preserving the structure and function of the Golgi apparatus and rough endoplasmic reticulum (ER) in vascular cells. Immunoimaging and green fluorescent protein-tagged-STAT5a protein localization studies showed the constitutive association of nonphosphorylated STAT5a, and to a lesser extent STAT5b, with the Golgi apparatus and of STAT5a with centrosomes in human pulmonary arterial endothelial and smooth muscle cells. Acute knockdown of STAT5a/b species using small interfering RNAs (siRNAs), including in the presence of an mRNA synthesis inhibitor (5,6-dichloro-1-β-d-ribofuranosylbenzimidazole), produced a dramatic phenotype within 1 day, consisting of dilatation and fragmentation of Golgi cisternae, a marked tubule-to-cyst change in the ER, increased accumulation of reticulon-4 (RTN4)/Nogo-B and atlastin-3 (ATL3) at cyst-zone boundaries, cystic separation of the outer and inner nuclear membranes, accompanied by scalloped/lunate distortion of the nucleus, with accumulation of RTN4 on convex sides of distorted nuclei. These cells showed inhibition of vesicular stomatitis virus G protein glycoprotein trafficking, mitochondrial fragmentation, and reduced mitochondrial function. STAT5a/b(-/-) mouse embryo fibroblasts also showed altered ER/Golgi dynamics. RTN4 knockdown using siRNA did not affect development of the cystic phenotype; ATL3 siRNA led to effacement of cyst-zone boundaries. In magnetic-bead cross-immunopanning assays, ATL3 bound both STAT5a and STAT5b. Remarkably, this novel cystic ER/lunate nucleus phenotype was characteristic of vascular cells in arterial lesions of idiopathic pulmonary hypertension, an unrelentingly fatal human disease. These data provide evidence of a STAT-family protein regulating the structure of a cytoplasmic organelle and implicate this mechanism in the pathogenesis of a human disease.
AuthorsJason E Lee, Yang-Ming Yang, Feng-Xia Liang, Daniel J Gough, David E Levy, Pravin B Sehgal
JournalAmerican journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 302 Issue 5 Pg. C804-20 (Mar 01 2012) ISSN: 1522-1563 [Electronic] United States
PMID22159083 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • G protein, vesicular stomatitis virus
  • Membrane Glycoproteins
  • Myelin Proteins
  • Nogo Proteins
  • RNA, Small Interfering
  • RTN4 protein, human
  • Rtn4 protein, mouse
  • STAT5 Transcription Factor
  • STAT5A protein, human
  • STAT5B protein, human
  • Tumor Suppressor Proteins
  • Viral Envelope Proteins
  • Dichlororibofuranosylbenzimidazole
Topics
  • Animals
  • Cattle
  • Cell Nucleus (metabolism)
  • Cells, Cultured
  • Centrosome (metabolism, ultrastructure)
  • Cytoplasm (metabolism)
  • Dichlororibofuranosylbenzimidazole (chemistry)
  • Endoplasmic Reticulum (metabolism, ultrastructure)
  • Endothelial Cells
  • Familial Primary Pulmonary Hypertension
  • Golgi Apparatus (metabolism, ultrastructure)
  • Humans
  • Hypertension, Pulmonary (metabolism)
  • Membrane Glycoproteins
  • Mice
  • Microscopy, Electron
  • Myelin Proteins (metabolism)
  • Myocytes, Smooth Muscle
  • Nogo Proteins
  • Protein Transport
  • Pulmonary Artery (cytology)
  • RNA, Small Interfering
  • STAT5 Transcription Factor (genetics, metabolism)
  • Tumor Suppressor Proteins (genetics, metabolism)
  • Viral Envelope Proteins

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