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Featured researches published by Khalequz Zaman.


Molecular Pharmacology | 2006

S-Nitrosylating Agents: A Novel Class of Compounds That Increase Cystic Fibrosis Transmembrane Conductance Regulator Expression and Maturation in Epithelial Cells

Khalequz Zaman; Silvia Carraro; Joseph Doherty; Edward M. Henderson; Elizabeth Lendermon; Lei Liu; George M. Verghese; Molly Zigler; Mark M. Ross; Edward Park; Lisa A. Palmer; Allan Doctor; Jonathan S. Stamler; Benjamin Gaston

The endogenous bronchodilator, S-nitrosoglutathione (GSNO), increases expression, maturation, and function of both the wild-type and the ΔF508 mutant of the cystic fibrosis transmembrane conductance regulatory protein (CFTR). Though transcriptional mechanisms of action have been identified, GSNO seems also to have post-transcriptional effects on CFTR maturation. Here, we report that 1) GSNO is only one of a class of S-nitrosylating agents that, at low micromolar concentrations, increase ΔF508 and wild-type CFTR expression and maturation; 2) NO itself (at these concentrations) and 8-bromocyclic GMP are minimally active on CFTR; 3) a novel agent, S-nitrosoglutathione diethyl ester, bypasses the need for GSNO bioactivation by γ-glutamyl transpeptidase to increase CFTR maturation; 4) surprisingly, expression—but not S-nitrosylation—of cysteine string proteins (Csp) 1 and 2 is increased by GSNO; 5) the effect of GSNO to increase full maturation of wild-type CFTR is inhibited by Csp silencing (si)RNA; 6) proteins relevant to CFTR trafficking are SNO-modified, and SNO proteins traffic through the endoplasmic reticulum (ER) and Golgi after GSNO exposure; and 7) GSNO alters the interactions of ΔF508 CFTR with Csp and Hsc70 in the ER and Golgi. These data suggest that GSNO is one of a class of S-nitrosylating agents that act independently of the classic NO radical/cyclic GMP pathway to increase CFTR expression and maturation. They also suggest that the effect of GSNO is dependent on Csp and on intracellular SNO trafficking. We speculate that these data will be of relevance to the development of NO donor-based therapies for CF.


Proceedings of the National Academy of Sciences of the United States of America | 2010

Hsp 70/Hsp 90 organizing protein as a nitrosylation target in cystic fibrosis therapy

Nadzeya V. Marozkina; Sean Yemen; Molly Borowitz; Lei Liu; Melissa Plapp; Fei Sun; Rafique Islam; Petra Erdmann-Gilmore; R. Reid Townsend; Cheryl F. Lichti; Sneha Mantri; Phillip W. Clapp; Scott H. Randell; Benjamin Gaston; Khalequz Zaman

The endogenous signaling molecule S-nitrosoglutathione (GSNO) and other S-nitrosylating agents can cause full maturation of the abnormal gene product ΔF508 cystic fibrosis (CF) transmembrane conductance regulator (CFTR). However, the molecular mechanism of action is not known. Here we show that Hsp70/Hsp90 organizing protein (Hop) is a critical target of GSNO, and its S-nitrosylation results in ΔF508 CFTR maturation and cell surface expression. S-nitrosylation by GSNO inhibited the association of Hop with CFTR in the endoplasmic reticulum. This effect was necessary and sufficient to mediate GSNO-induced cell-surface expression of ΔF508 CFTR. Hop knockdown using siRNA recapitulated the effect of GSNO on ΔF508 CFTR maturation and expression. Moreover, GSNO acted additively with decreased temperature, which promoted mutant CFTR maturation through a Hop-independent mechanism. We conclude that GSNO corrects ΔF508 CFTR trafficking by inhibiting Hop expression, and that combination therapies—using differing mechanisms of action—may have additive benefits in treating CF.


Methods in Enzymology | 2005

S‐Nitrosothiol Formation

Jeannean Carver; Allan Doctor; Khalequz Zaman; Benjamin Gaston

Protein and peptide S-nitrosothiols (SNOs) are involved in guanylate cyclase-independent signaling associated with nitric oxide synthase (NOS) activation. As a general rule, SNO formation requires the presence of an electron acceptor such as Cu2+. Various proteins have been identified that catalyze SNO formation, including NOS itself, ceruloplasmin, and hemoglobin. Biochemical evidence suggests the existence of other SNO synthases and NOS-associated proteins involved in SNO formation following NOS activation. Indeed, both hydrophilic and hydrophobic consensus motifs have been identified that favor protein S-nitrosylation. Inorganic SNO formation appears also to occur in biological systems at low pH levels and/or in membranes. Once formed, SNOs localized to specific cellular compartments signal specific effects, ranging from gene regulation to ion channel gating. Indeed, the number of cellular and physiological functions appreciated to be regulated through SNO synthesis, localization, and catabolism is increasing. Although research into SNO biosynthesis is in its infancy, the importance of this field of biochemistry has been confirmed repeatedly by investigators from a broad spectrum of disciplines.


Biochemical and Biophysical Research Communications | 2001

S-nitrosoglutathione increases cystic fibrosis transmembrane regulator maturation.

Khalequz Zaman; Marianne McPherson; John W. Vaughan; John F. Hunt; Filipa Mendes; Benjamin Gaston; Lisa A. Palmer


Biochemical Journal | 2004

Concentration-dependent effects of endogenous S-nitrosoglutathione on gene regulation by specificity proteins Sp3 and Sp1.

Khalequz Zaman; Lisa A. Palmer; Allan Doctor; John F. Hunt; Benjamin Gaston


American Journal of Respiratory Cell and Molecular Biology | 2006

Endogenous S-nitrosoglutathione modifies 5-lipoxygenase expression in airway epithelial cells.

Khalequz Zaman; Marie H. Hanigan; Alison Smith; John W. Vaughan; Timothy L. Macdonald; David R. Jones; John F. Hunt; Benjamin Gaston


American Journal of Physiology-lung Cellular and Molecular Physiology | 2006

S-nitrosothiols regulate cell-surface pH buffering by airway epithelial cells during the human immune response to rhinovirus

Silvia Carraro; Joseph Doherty; Khalequz Zaman; Iain Gainov; Ronald B. Turner; John W. Vaughan; John F. Hunt; Javier Márquez; Benjamin Gaston


European Respiratory Journal | 2013

Airway epithelial hemoglobin β regulates ciliary endothelial NOS

Nadzeya Marozkina; Giovanni Piedimonte; Lesly Cottrell; Vinod Jyothikumar; Amasi Periasamy; Khalequz Zaman; Adam C. Straub; Scott H. Randell; Benjamin Gaston


american thoracic society international conference | 2012

Airflow-Associated Nitric Oxide Synthase Activation Is A Critical Determinant Of Human Airway S-Nitrosothiol Levels

Nadzeya V. Marozkina; Khalequz Zaman; Vitali I. Stsiapura; Alix Paget-Brown; Scott Dwyer; Michael D. Davis; Stephen J. Lewis; Sally E. Wenzel; Serpil C. Erzurum; W. G. Teague; Suzy Comhair; Benjamin Gaston


american thoracic society international conference | 2011

Therapeutic Ultrasound Increases DF508 CFTR Expression In Human Airway Epithelial Cells

Khalequz Zaman; K. R. Greenberg; A Rahman; Sean Yemen; Benjamin Gaston

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Benjamin Gaston

University of Virginia Health System

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Sean Yemen

University of Virginia

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Allan Doctor

Washington University in St. Louis

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Scott H. Randell

University of North Carolina at Chapel Hill

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Lei Liu

University of Virginia

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