PubMed Health⌕ Search

Biomedical subjects

Derek W Abbott

Publications and source records attributed to Derek W Abbott.

6 recordsLinked to original sources
PubMed2025

Restraint of inflammasome-driven cytokine responses through the mRNA stability protein TTP.

Activation of the NLRP3 inflammasome causes extensive disturbance of cellular homeostasis, with Golgi disruption, mitochondrial dysfunction, and changes in intracellular ion concentration occurring rapidly upon stimulation. Given this, it would seem near certain that these changes might also globally affect cellular signaling pathways, yet few, if any, studies have explored this possibility. Here, we combine genomics and phosphoproteomics to identify inhibition of the ERK1/2 MAP kinase signaling cascade upon inflammasome stimulation. This loss of ERK1/2 activity results in rapid inactivation of the mRNA decay-promoting protein tristetraprolin (TTP), with loss of TTP promoting subsequent increased release of cytokines upon pyroptosis. Further, we observe significantly increased levels of TTP expression in patients with inflammatory bowel disease, a disease for which altered cytokine expression is a key driver of pathogenesis. Inflammasome activation thus rapidly inactivates a pathway designed to suppress cytokine release, potentially exacerbating hyperinflammatory states, including those involved in autoinflammatory disease.

Inflammasomes↗
PubMed2005

The Mycobacterium tuberculosis serine/threonine kinases PknA and PknB: substrate identification and regulation of cell shape.

The Mycobacterium tuberculosis genome contains 11 serine/threonine kinase genes including two, pknA and pknB, that are part of an operon encoding genes involved in cell shape control and cell wall synthesis. Here we demonstrate that pknA and pknB are predominantly expressed during exponential growth, and that overexpression of these kinases slows growth and alters cell morphology. We determined the preferred substrate motifs of PknA and PknB, and identified three in vivo substrates of these kinases: PknB; Wag31, an ortholog of the cell division protein DivIVA; and Rv1422, a conserved protein of unknown function. Expression of different alleles of wag31 in vivo alters cell shape, in a manner dependent on the phosphoacceptor residue in the protein produced. Partial depletion of pknA or pknB results in narrow, elongated cells. These data indicate that signal transduction mediated by these kinases is a novel mechanism for the regulation of cell shape in mycobacteria, one that may be conserved among gram-positive bacteria.

Amino Acid Sequence↗
PubMed2004

The Crohn's disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO.

BACKGROUND: Crohn's disease is an autoimmune inflammatory disorder of the gastrointestinal tract and is characterized clinically by dysregulation of both pro-inflammatory and anti-inflammatory cytokine signaling networks. The function of the Crohn's disease protein, NOD2, highlights the biphasic nature of the pathology of Crohn's disease. NOD2 can both strongly activate and negatively attenuate NF-kB signaling. The biochemical mechanism for this dual function of NOD2 is unknown. RESULTS: We demonstrate that NOD2 activation leads to ubiquitinylation of NEMO, a key component of the NF-kB signaling complex. This ubiquitinylation is agonist dependant, and it does not regulate proteosomal destruction of NEMO. We show the NOD2-dependent ubiquitinylation of NEMO is dependent on the scaffolding protein kinase RIP2. Crohn's disease-associated polymorphisms of NOD2 show a decreased ability to bind RIP2, and this decreased ability to bind RIP2 correlates with a decreased ability to ubiquitinylate NEMO. We map the site of NEMO ubiquitinylation to a novel NEMO ubiquitinylation site (Lysine 285) and show that this ubiquityinylation occurs in vivo. Lastly, we show functionally that RIP2-induced ubiquitinylation of NEMO is at least in part responsible for RIP2-mediated NF-kB activation. CONCLUSIONS: These data suggest that this novel mode of regulation of the NF-kB signaling pathway could be a factor underlying the pathogenesis of Crohn's disease.

Amino Acid Sequence↗
PubMed2004

A rapid method for determining protein kinase phosphorylation specificity.

Selection of target substrates by protein kinases is strongly influenced by the amino acid sequence surrounding the phosphoacceptor site. Identification of the preferred peptide phosphorylation motif for a given kinase permits the production of efficient peptide substrates and greatly simplifies the mapping of phosphorylation sites in protein substrates. Here we describe a combinatorial peptide library method that allows rapid generation of phosphorylation motifs for serine/threonine kinases.

Amino Acid Motifs↗
PubMed2003

Cervical cancer screening: from the Papanicolaou smear to the vaccine era.

In the next 20 years, cervical cancer screening will have evolved through four phases. The first was traditional screening, which has been associated with a two-thirds reduction in cancer incidence and death rates in the last 50 years and currently is ending. We are entering a second phase, human papillomavirus (HPV) testing, for managing cytologic abnormalities and possibly for primary screening. A third phase, new in development, proposes the use of host biomarkers (or combinations thereof) as either surrogates of HPV infection or, potentially, indicators to assess cancer risk and concentrate available resources on a subset of women. The fourth and, likely, final phase will be screening in an era of vaccines. If HPV vaccines are successful, the pool of at-risk individuals and the prevalence of papillomaviruses that place them at risk will gradually shrink. In this climate, screening strategies that target HPVs alone (as opposed to cytologic testing) may become more economical. If so, previous strategies may become obsolete as the balance of cervical cancer prevention shifts from traditional screening to primary prevention coupled with HPV testing.

Biomarkers, Tumor↗