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Carlesso N.,Herman lls Center For Pediatric Research | Carlesso N.,Indiana University | Cardoso A.A.,Indiana University
Current Opinion in Hematology | Year: 2010

Purpose of review: In the postnatal life, hematopoietic stem cell (HSC) niches are specialized microenvironments in the bone marrow that are essential for the maintenance and function of HSCs. The purpose of this review is to discuss the concept of HSC niche in light of recent studies that broaden its complexity and better define its molecular regulation. Also, we will discuss recent studies addressing the impact of leukemia development on HSC regulation and normal hematopoiesis, while discussing the potential regulation of leukemia-initiating cells by bone marrow niches. Recent findings: Recent studies have identified new cellular and molecular components of the HSC niche and highlighted reciprocal interactions between the hematopoietic cells and their niches. These studies indicate that the HSC niche is not constituted by a single cell type but rather should be considered as a multicellular functional unit. Finally, advances have been made that provide promising insights into the the instructive role of the bone marrow microenvironment in hematological malignancies. Summary: Increasing insights into the cell-cell cross talk between the hematopoietic system and its microenvironment in the bone marrow, and in particular in the interplay of HSCs with their niche(s), should provide new tools for combinatorial therapies in bone marrow failure and bone marrow cancers. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Safa A.R.,Indiana University | Pollok K.E.,Indiana University | Pollok K.E.,Herman lls Center For Pediatric Research
Cancers | Year: 2011

Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor and critical anti-apoptotic regulator that inhibits tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well as chemotherapy-triggered apoptosis in malignant cells. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 in a ligand-dependent and-independent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. Moreover, c-FLIPL and c-FLIPS are known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective signaling molecules. Upregulation of c-FLIP has been found in various tumor types, and its downregulation has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. For example, small interfering RNAs (siRNAs) that specifically knockdown the expression of c-FLIPL in diverse human cancer cell lines augmented TRAIL-induced DISC recruitment and increased the efficacy of chemotherapeutic agents, thereby enhancing effector caspase stimulation and apoptosis. Moreover, small molecules causing degradation of c-FLIP as well as decreasing mRNA and protein levels of c-FLIPL and c-FLIPS splice variants have been found, and efforts are underway to develop other c-FLIP-targeted cancer therapies. This review focuses on (1) the functional role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and drug resistance; (2) the molecular mechanisms that regulate c-FLIP expression; and (3) strategies to inhibit c-FLIP expression and function. © 2011 by the authors; licensee MDPI, Basel, Switzerland. Source

Nabinger S.C.,Indiana University | Chan R.J.,Herman lls Center For Pediatric Research | Chan R.J.,Indiana University
Current Opinion in Hematology | Year: 2012

Purpose of review: The protein tyrosine phosphatase Shp2 is encoded by PTPN11 and positively regulates physiologic hematopoiesis. Mutations of PTPN11 cause the congenital disorder Noonan syndrome and pathologically promote human leukemias. Given the high frequency of PTPN11 mutations in human disease, several animal models have been generated to investigate Shp2 in hematopoietic stem cell (HSC) function and leukemic transformation. Recent findings: Two independent animal models bearing knockout of Shp2 in hematopoietic tissues clearly demonstrate the necessity of Shp2 in HSC repopulating capacity. Reduced HSC quiescence and increased apoptosis accounts for diminished HSC function in the absence of Shp2. The germline mutation Shp2D61G enhances HSC activity and induces myeloproliferative disease (MPD) in vivo by HSC transformation. The somatic mutation Shp2D61Y produces MPD in vivo but fails to induce acute leukemia, whereas somatic Shp2E76K produces MPD in vivo that transforms into full-blown leukemia. HSCs expressing Shp2D61Y do not generate MPD in recipient animals upon transplantation, whereas Shp2E76K-expressing HSCs yield MPD as well as acute leukemia in recipient animals. The mechanisms underlying the unique functions of Shp2D61Y and Shp2E76K in HSC transformation and leukemogenesis continue to be under investigation. Summary: Further understanding of the physiologic and pathologic role of Shp2 in hematopoiesis and leukemogenesis, respectively, will yield information needed to develop therapeutic strategies targeted to Shp2 in human disease. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Periyasamy S.,University of Toledo | Hinds T.,University of Toledo | Shemshedini L.,University of Toledo | Shou W.,Herman lls Center For Pediatric Research | Sanchez E.R.,University of Toledo
Oncogene | Year: 2010

Prostate cancer (PCa) growth is dependent on androgens and on the androgen receptor (AR), which acts by modulating gene transcription. Tetratricopeptide repeat (TPR) proteins (FKBP52, FKBP51 and Cyp40) interact with AR in PCa cells, suggesting roles in AR-mediated gene transcription and cell growth. We report here that FKBP51 and Cyp40, but not FKBP52, are significantly elevated in PCa tissues and in androgen-dependent (AD) and androgen-independent (AI) cell lines. Overexpression of FKBP51 in AD LNCaP cells increased AR transcriptional activity in the presence and absence of androgen, whereas siRNA knockdown of FKBP51 dramatically decreased AD gene transcription and proliferation. Knockdown of Cyp40 also inhibited androgen-mediated transcription and growth in LNCaP cells. However, disruption of FKBP51 and Cyp40 in AI C4-2 cells caused only a small reduction in proliferation, indicating that Cyp40 and FKBP51 predominantly regulate AD cell proliferation. Under knockdown conditions, the inhibitory effects of TPR ligands, cyclosporine A (CsA) and FK506, on AR activity were not observed, indicating that Cyp40 and FKBP51 are the targets of CsA and FK506, respectively. Our findings show that FKBP51 and Cyp40 are positive regulators of AR that can be selectively targeted by CsA and FK506 to achieve inhibition of androgen-induced cell proliferation. These proteins and their cognate ligands thus provide new strategies in the treatment of PCa. © 2010 Macmillan Publishers Limited All rights reserved. Source

Yamada M.,University of North Carolina at Chapel Hill | Gomez J.C.,University of North Carolina at Chapel Hill | Chugh P.E.,University of North Carolina at Chapel Hill | Lowell C.A.,University of California at San Francisco | And 4 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011

Rationale: Neutrophils are usually the first circulating leukocytes to respond during bacterial pneumonia. Their expression of oxidants, proteases, and other mediators present in granules is well documented, but their ability to produce mediators through transcription and translation after migration to an inflammatory site has been appreciated only more recently. Interferon (IFN)-γ is a cytokine with many functions important in host defense and immunity. Objectives: To examine the expression and function of IFN-γ in bacterial pneumonias. Methods: IFN-γ mRNA and protein were measured in digests of mouse lungs with 24-hour bacterial pneumonia. Bacterial clearance was studied with IFN-γ-deficient mice. Measurements and Main Results: Streptococcus pneumoniae and Staphylococcus aureus each induce expression of IFN-γ mRNA and protein by neutrophils by 24 hours. Only neutrophils that have migrated into pneumonic tissue produce IFN-γ. Deficiency of Hck/Fgr/Lyn, Rac2, or gp91phox prevents IFN-γ production. IFN-γ enhances bacterial clearance and is required for formation of neutrophil extracellular traps. In contrast, Pseudomonas aeruginosa and Escherichia coli induce production of IFN-γ mRNA but not protein. During pneumonia induced by E. coli but not S. pneumoniae, neutrophils produce microRNAs that target the 3′ untranslated region of the IFN-γ gene. Conclusions: S. pneumoniae and S. aureus, but not P. aeruginosa and E. coli, induce emigrated neutrophils to produce IFN-γ within 24 hours. Hck/Fgr/Lyn, Rac2, and NADPH oxidase are required for IFN-γ production. IFN-γ facilitates bacterial clearance at least in part through regulating formation of neutrophil extracellular traps. Differential expression by neutrophils of microRNAs that target the 3′ untranslated region of the IFN-γ gene may contribute to the pathogen-specific regulation of translation. Source

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