Restoration of Adenosine Deaminase-Deficient Human Thymocyte Development In Vitro by Inhibition of Deoxynucleoside Kinases

Joachims, Michelle L.; Marble, Patrick; Laurent, Aletha B.; Pastuszko, Peter; Paliotta, Marco; Blackburn, Michael R.; Thompson, Linda F.

doi:10.4049/jimmunol.181.11.8153

Cited by 12 publications

(14 citation statements)

References 52 publications

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“…The phosphorylation of dAdo to dATP requires two key enzymes: DCK and AK (12, 16). To determine whether these pathways were activated in the lungs of Ada –/– mice, the expression of DCK and AK was examined by Western blot and immunostaining on P42, a stage when air‐space enlargement is prominent (5).…”

Section: Resultsmentioning

confidence: 99%

Hypoxia‐induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease

Weng¹,

Karmouty‐Quintana²,

Garcia-Morales

et al. 2013

FASEB j.

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Chronic obstructive pulmonary disease (COPD) is characterized by persistent inflammation and tissue remodeling and is a leading cause of death in the United States. Increased apoptosis of pulmonary epithelial cells is thought to play a role in COPD development and progression. Identification of signaling pathways resulting in increased apoptosis in COPD can be used in the development of novel therapeutic interventions. Deoxyadenosine (dAdo) is a DNA breakdown product that amplifies lymphocyte apoptosis by being phosphorylated to deoxyadenosine triphosphate (dATP). dAdo is maintained at low levels by adenosine deaminase (ADA). This study demonstrated that mice lacking ADA developed COPD manifestations in association with elevated dAdo and dATP levels and increased apoptosis in the lung. Deoxycitidine kinase (DCK), a major enzyme for dAdo phosphorylation, was up-regulated in mouse and human airway epithelial cells in association with air-space enlargement. Hypoxia was identified as a novel regulator of DCK, and inhibition of DCK resulted in diminished dAdo-mediated apoptosis in the lungs. Our results suggest that activating the dAdo-DCK-dATP pathway directly results in increased apoptosis in the lungs of mice with air-space enlargement and suggests a novel therapeutic target for the treatment of COPD.

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Section: Resultsmentioning

confidence: 99%

Hypoxia‐induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease

Weng¹,

Karmouty‐Quintana²,

Garcia-Morales

et al. 2013

FASEB j.

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“…However, the primary cause of toxicity in developing human thymocytes is the accumulation of deoxyATP which triggers mitochondrial-dependent apoptosis. 37 …”

Section: Paradoxical Effects Of Pka On T Cells Survivalmentioning

confidence: 99%

Regulation of Lymphocyte Function by Adenosine

Linden¹,

Cekic²

2012

ATVB

129

103

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Adenosine regulates the interaction between lymphocytes and the vasculature and is important for controlling lymphocyte trafficking in response to tissue injury or infection. Adenosine can blunt the effects of T cell receptor (TCR) activation primarily by activating adenosine A2A receptors (A2AR) and signaling via cyclic AMP and protein kinase A (PKA). PKA reduces proximal TCR signaling by phosphorylation of C-terminal Src kinase (Csk), nuclear factor of activated T cells (NF-AT) and cyclic AMP response element binding protein (CREB). PKA activation can either enhance or inhibit the survival of T cells depending on the strength and duration of signaling. Inducible enzymes such as CD73 and CD39 regulate adenosine formation and degradation in vivo. The extravasation of lymphocytes through blood vessels is influenced by A2AR-mediated suppression of Intercellular Adhesion Molecule 1 (ICAM) expression on lymphocytes and diminished production of IFNγ and IFNγ-inducible chemokines that are chemotactic to activated lymphocytes. Adenosine also decreases the barrier function of vascular endothelium by activating A2BRs. In sum, adenosine signaling is influenced by tissue inflammation and injury through induction of receptors and enzymes and has generally inhibitory effects on lymphocyte migration into inflamed tissues due to PKA-mediated effects on adhesion molecules, IFNγ production and endothelial barrier function.

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“…Loss of adenosine deaminase leads to the accumulation of high intracellular levels of dATP that, by being toxic to developing lymphocytes, cause severe combined immunodeficiency in humans (2). Because dATP accumulation requires the enzymatic activity of dCK and adenosine kinase, small-molecule inhibitors of these kinases have been recently suggested as a new therapeutic approach for ADA-deficient patients (30). However, our findings suggest that complete inhibition of dCK activity may not be desirable, given the requirement for this kinase in normal lymphopoiesis.…”

Section: Why Do Developing Lymphocytes Depend On the Deoxyribonucleosidementioning

confidence: 99%

Requirement for deoxycytidine kinase in T and B lymphocyte development

Toy¹,

Austin²,

Liao³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

103

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Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway that recycles products of DNA degradation. dCK phosphorylates and therefore activates nucleoside analog prodrugs frequently used in cancer, autoimmunity, and viral infections. In contrast to its well established therapeutic relevance, the biological function of dCK remains enigmatic. Highest levels of dCK expression are found in thymus and bone marrow, indicating a possible role in lymphopoiesis. To test this hypothesis we generated and analyzed dCK knockout (KO) mice. dCK inactivation selectively and profoundly affected T and B cell development. A 90-fold decrease in thymic cellularity was observed in the dCK KO mice relative to wild-type littermates. Lymphocyte numbers in the dCK KO mice were 5-to 13-fold below normal values. The severe impact of dCK inactivation on lymphopoiesis was unexpected given that nucleoside salvage has been thought to play a limited, "fine-tuning" role in regulating deoxyribonucleotide triphosphate pools produced by the de novo pathway. The dCK KO phenotype challenges this view and indicates that, in contrast to the great majority of other somatic cells, normal lymphocyte development critically requires the deoxyribonucleoside salvage pathway.

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Restoration of Adenosine Deaminase-Deficient Human Thymocyte Development In Vitro by Inhibition of Deoxynucleoside Kinases

Cited by 12 publications

References 52 publications

Hypoxia‐induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease

Hypoxia‐induced deoxycytidine kinase expression contributes to apoptosis in chronic lung disease

Regulation of Lymphocyte Function by Adenosine

Requirement for deoxycytidine kinase in T and B lymphocyte development

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