There is emerging evidence that mammalian target of Rapamycin (mTOR) complexes play important roles in IFN-signaling and mRNA translation of interferon-stimulated genes (ISGs), by controlling the ...function of downstream effector pathways. We provide evidence that IFN-induced ISG expression is defective in cells with targeted disruption of the Rictor gene, a key component of the mTORC2 complex. Our studies demonstrate that there is defective expression of several IFN-inducible genes that mediate important biological functions, including anti-proliferative, antiviral and pro-apoptotic responses. Importantly, we also found that Rictor and Sin1 play essential roles in the generation of the suppressive effects of IFN alpha on malignant erythroid precursors from patients with myeloproliferative neoplasms (MPNs), suggesting unique roles for such complexes in the IFN-system. Altogether, our data provide evidence for critical and essential roles for Rictor/Sin1 complexes in IFN-signaling and the control of IFN-responses.
Communication and the Work-Life Balancing Act: Intersections across Identities, Genders, and Cultures offers scholarly research related to work-life balance in today’s environment, with a particular ...focus on the fields of communication and gender studies. The chapters examine the choices, challenges, and gendered experiences that women and men face as they navigate structures of work, domestic duties, and childcare in search of balance. Underpinning this text is the notion that work-life balance affects everyone but is experienced differently through the intersections of sex, age, gender, socioeconomic status, and race. Recommended for scholars of communication, gender studies, organizational communication, sociology, and family communication.
Presence and effects of pharmaceutical and personal care products on the Baca National Wildlife Refuge, Colorado Zenobio, Jenny E; Brian C. SanchezauthorU.S. Fish & Wildlife Service, Environmental Contaminants Program, Lakewood, CO 80255, USA; Jessica K. LeetauthorPurdue University, Department of Forestry and Natural Resources, West Lafayette, IN 47907, USAUniversity of South Carolina, Department of Environmental Health Sciences, Columbia, SC 29208, USA ...
2015
Journal Article
The mechanisms by which interferon α (IFN-α) induces antileukemic responses in chronic myelogenous leukemia (CML) cells are not known. We examined whether a member of the protein kinase C (PKC) ...family of proteins, PKC-δ, is activated during treatment of BCR-ABL cells with IFN-α and participates in the induction of interferon responses.
Immunoblots and immune complex kinase assays were performed to study the phosphorylation and activation of PKC-δ in response to IFN-α in CML-derived cell lines. The effects of pharmacological inhibition of PKC-δ on the suppressive effects of IFN-α on leukemic CFU-GM progenitors from CML patients were assessed by clonogenic assays in methylcellulose.
IFN-α treatment of the sensitive CML-derived KT-1 cell line resulted in phosphorylation of PKC-δ and activation of its kinase domain. Such phosphorylation/activation of PKC-δ was required for phosphorylation of Stat1 on serine 727, as inhibition of PKC-δ activity blocked the IFN-α–dependent serine phosphorylation of Stat1 and IFN-α–inducible gene transcription. IFN-α treatment strongly inhibited leukemic CFU-GM progenitor colony fromation from bone marrow or peripheral blood of patients with CML, and such inhibition was reversed by concomitant treatment of the cells with the PKC-δ pharmacologic inhibitor rottlerin.
Taken altogether, our data demonstrate that PKC-δ plays a critical role in Type I IFN signaling in BCR-ABL expressing cells, acting as a serine kinase for Stat1, to regulate transcriptional activation of interferon-regulated genes and induction of antileukemic responses.
Type I interferons (IFNs) are cytokines with diverse biological properties, including antiviral, growth inhibitory, and immunomodulatory effects. Although several signaling pathways are activated ...during engagement of the type I IFN receptor and participate in the induction of IFN responses, the mechanisms of generation of specific signals for distinct biological effects remain to be elucidated. We provide evidence that a novel member of the protein kinase C (PKC) family of proteins is rapidly phosphorylated and activated during engagement of the type I IFN receptor. In contrast to other members of the PKC family that are also regulated by IFN receptors, PKCeta does not regulate IFN-inducible transcription of interferon-stimulated genes or generation of antiviral responses. However, its function promotes cell cycle arrest and is essential for the generation of the suppressive effects of IFNalpha on normal and leukemic human myeloid (colony-forming unit-granulocyte macrophage) bone marrow progenitors. Altogether, our studies establish PKCeta as a unique element in IFN signaling that plays a key and essential role in the generation of the regulatory effects of type I IFNs on normal and leukemic hematopoiesis.
Type I interferons (IFNs) are cytokines with diverse biological properties, including antiviral, growth inhibitory, and immunomodulatory
effects. Although several signaling pathways are activated ...during engagement of the type I IFN receptor and participate in
the induction of IFN responses, the mechanisms of generation of specific signals for distinct biological effects remain to
be elucidated. We provide evidence that a novel member of the protein kinase C (PKC) family of proteins is rapidly phosphorylated
and activated during engagement of the type I IFN receptor. In contrast to other members of the PKC family that are also regulated
by IFN receptors, PKCη does not regulate IFN-inducible transcription of interferon-stimulated genes or generation of antiviral
responses. However, its function promotes cell cycle arrest and is essential for the generation of the suppressive effects
of IFNα on normal and leukemic human myeloid (colony-forming unit-granulocyte macrophage) bone marrow progenitors. Altogether,
our studies establish PKCη as a unique element in IFN signaling that plays a key and essential role in the generation of the
regulatory effects of type I IFNs on normal and leukemic hematopoiesis.
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