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PIKfyve: Partners, significance, debates and paradoxes.

ABSTRACT: Key components of membrane trafficking and signaling machinery in eukaryotic cells are proteins that bind or synthesize phosphoinositides. PIKfyve, a product of an evolutionarily conserved single-copy gene has both these features. It binds to membrane phosphatidylinositol (PtdIns)3P and synthesizes PtdIns(3,5)P2 and PtdIns5P. Molecular functions of PIKfyve are elusive but recent advances are consistent with a key role in the course of endosomal transport. PIKfyve dysfunction induces endosome enlargement and profound cytoplasmic vacuolation, likely as a result of impaired normal endosome processing and membrane exit out of endosomes. Multicellular organisms with genetically impaired function of PIKfyve or that of the PIKfyve protein partners regulating PtdIns(3,5)P2 homeostasis display severe disorders, including embryonic/perinatal death. This review describes recent advances on PIKfyve functionality in higher eukaryotes, with particular reference to biochemical and genetic insights in PIKfyve protein partners.

SUBMITTER: Shisheva A

PROVIDER: S-EPMC2491398 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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PIKfyve: Partners, significance, debates and paradoxes.

Shisheva Assia A

Cell biology international 20080125 6

Key components of membrane trafficking and signaling machinery in eukaryotic cells are proteins that bind or synthesize phosphoinositides. PIKfyve, a product of an evolutionarily conserved single-copy gene has both these features. It binds to membrane phosphatidylinositol (PtdIns)3P and synthesizes PtdIns(3,5)P2 and PtdIns5P. Molecular functions of PIKfyve are elusive but recent advances are consistent with a key role in the course of endosomal transport. PIKfyve dysfunction induces endosome enl ...[more]

PMID: 18304842

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Project description:The mechanisms that underlie various inflammation paradoxes, metabolically healthy obesity, and increased inflammations after inflammatory cytokine blockades and deficiencies remain poorly determined. We performed an extensive -omics database mining, determined the expressions of 1367 innate immune regulators in 18 microarrays after deficiencies of 15 proinflammatory cytokines/regulators and eight microarray datasets of patients receiving Mab therapies, and made a set of significant findings: 1) proinflammatory cytokines/regulators suppress the expressions of innate immune regulators; 2) upregulations of innate immune regulators in the deficiencies of IFNγ/IFNγR1, IL-17A, STAT3 and miR155 are more than that after deficiencies of TNFα, IL-1β, IL-6, IL-18, STAT1, NF-kB, and miR221; 3) IFNγ, IFNγR and IL-17RA inhibit 10, 59 and 39 proinflammatory cytokine/regulator pathways, respectively; in contrast, TNFα, IL-6 and IL-18 each inhibits only four to five pathways; 4) The IFNγ-promoted and -suppressed innate immune regulators have four shared pathways; the IFNγR1-promoted and -suppressed innate immune regulators have 11 shared pathways; and the miR155-promoted and -suppressed innate immune regulators have 13 shared pathways, suggesting negative-feedback mechanisms in their conserved regulatory pathways for innate immune regulators; 5) Deficiencies of proinflammatory cytokine/regulator-suppressed, promoted programs share signaling pathways and increase the likelihood of developing 11 diseases including cardiovascular disease; 6) There are the shared innate immune regulators and pathways between deficiency of TNFα in mice and anti-TNF therapy in clinical patients; 7) Mechanistically, up-regulated reactive oxygen species regulators such as myeloperoxidase caused by suppression of proinflammatory cytokines/regulators can drive the upregulation of suppressed innate immune regulators. Our findings have provided novel insights on various inflammation paradoxes and proinflammatory cytokines regulation of innate immune regulators; and may re-shape new therapeutic strategies for cardiovascular disease and other inflammatory diseases.

Project description:BackgroundThe notion of 'fact-free politics' is debated in Europe and the United States of America and has particular relevance for the use of evidence to underpin health and healthcare policies. To better understand how evidence on health and healthcare is used in the national policy-making process in the Netherlands, we explore how different statistics are used in various policy debates on health and healthcare in the Dutch government and parliament.MethodsWe chose eight ongoing policy debates as case studies representing the subject categories of morbidity, lifestyle, healthcare expenditure and healthcare outcomes, including (1) breast cancer screening rates, prevalence and incidence, (2) dementia prevalence and incidence, (3) prevalence of alcohol use by pregnant women, (4) mobility and school sports participation in children, (5) costs of smoking, (6) Dutch national healthcare expenditure, (7) hospital mortality rates, and (8) bedsore prevalence. Using selected keywords for each policy debate case, we performed a document search to identify documentation of the debates (2014-2016) on the websites of the Dutch government and parliament. We retrieved 163 documents and examined the policy debate cases through a content analyses approach.ResultsSources of the statistics used in policy debates were primarily government funded. We identified two distinct functions, i.e. rhetorical and managerial use of statistics. The function of the debate is rhetorical when the specific statistic is used for agenda-setting or to convince the reader of the importance of a topic. The function of the debate is managerial when statistics determine planning, monitoring or evaluation of policy. When evaluating a specific policy, applied statistics were mostly the result of routine or standardised data collection. When policy-makers use statistics for a managerial function, the policy debate mirrors terms derived from scientific debates.ConclusionWhile statistics used for rhetorical functions do not seem to invite critical reflection, when the function of the debate is managerial, i.e. to plan, monitor or evaluate healthcare, their construction does receive attention. Considering the current role of statistics in rhetorical and managerial debates, there is a need to be cautious of too much leniency towards the technocratic process in exchange for the democratic debate.

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PIKfyve: Partners, significance, debates and paradoxes.

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PIKfyve: Partners, significance, debates and paradoxes.

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