Erythrocyte formation occurs throughout life in response to cytokine signaling. We show that microRNA-451 (miR-451) regulates erythropoiesis in vivo. Mice lacking miR-451 display a reduction in hematrocrit, an erythroid differentiation defect, and ineffective erythropoiesis in response to oxidative stress. 14-3-3ζ, an intracellular regulator of cytokine signaling that is repressed by miR-451, is up-regulated in miR-451−/− erythroblasts, and inhibition of 14-3-3ζ rescues their differentiation defect. These findings reveal an essential role of 14-3-3ζ as a mediator of the proerythroid differentiation actions of miR-451, and highlight the therapeutic potential of miR-451 inhibitors.
Dietary restriction, including fasting, delays aging and has pro-longevity effects in a wide range of organisms, and so has been considered for cancer prevention and the treatment of certain solid tumor types [1][2][3][4][5][6] . Fasting can promote hematopoietic stem cell-based regeneration and reverse immunosuppression [7][8][9] , and has been reported to promote the anti-cancer effects of chemotherapy 5,10 . However, the responsiveness of hematopoietic malignancies to dietary restriction, including fasting, remains unknown.AML is the most common form of adult acute leukemia, whereas ALL is the most common form of cancer in children; ALL also occurs in adults [11][12][13] . Although treatment of pediatric ALL is highly effective, a sizeable number of patients are nonresponders who succumb to this disease. The outcome of ALL in adults is substantially worse than for pediatric ALL, with a 5-year survival rate of approximately 40% 12 . Additionally, some types of ALL have a much poorer prognosis than others 12 . New therapeutic targets and approaches need to be identified to treat these leukemias more effectively. Here we investigated whether and how fasting regulates the development of B-ALL, T-ALL and AML. RESULTSFasting selectively inhibits the development of ALL but not AML To extend our previous work on the extrinsic and metabolic regulation of hematopoietic stem cells and cancer development 14-22 , we studied the effects of fasting on leukemia development. Mice from several retrovirus transplantation acute leukemia models, including the N-Myc B-ALL model 23 , the activated Notch1 T-ALL model 24 and the MLL-AF9 AML model 25,26 , were placed on various dietary regimens. Strikingly, a regimen consisting of six cycles of 1 d of fasting, followed by 1 d of feeding, implemented 2 d after transplantation (Fig. 1a) completely inhibited B-ALL development. The fasted mice had 32.85 ± 5.16, 11.31 ± 5.42 and 0.48 ± 0.12% of leukemic GFP + cells in peripheral blood (PB) at 3, 5 and 7 weeks post-transplantation, respectively, as compared to 49.52 ± 5.75, 56.27 ± 9.36 and 67.68 ± 8.39% of GFP + cells of the control mice (Fig. 1b,c). Concordantly, the percentages of leukemic cells in the bone marrow (BM) and spleen (SP) and the numbers of white blood cells (WBCs) in PB were also dramatically lower in the fasted mice at 7 weeks posttransplantation (Fig. 1c,d).Next, we measured the distribution of B lymphoblastic cells and myeloid cells in the GFP + compartment of the B-ALL mice. Control mice with B-ALL had 65-80% of B220 + cells (pan B lineage marker) and 0.5-2% of Mac-1 + cells (myeloid lineage marker) in GFP + fractions of PB, BM and SP (Fig. 1e,f), indicative of fully developed B-ALL. By contrast, there were only 19-28% of B220 + cells and 5-12% of Mac-1 + in GFP + fractions in fasted mice (Fig. 1e,f), consistent with loss of the B-ALL phenotype. There was also a higher percentage of New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered ...
fibrillar deposits known as Lewy bodies and neurites are distinct signatures of Parkinson's disease. We demonstrate the hierarchical self-assembly of aS fibrils into mesoscopic structures in vitro. The morphology of these structures is well-defined and depends on the physicochemical conditions at which the aggregates are formed. The observed phenomenon seems to be governed by the interplay between long ranged repulsion and short ranged attraction. Once the multiple negative charges on the fibrils are sufficiently screened at high enough salt concentration or neutrilized at appropriate pH level the electrostatic repulsion is minmized allowing the short range attraction (hydrophobic) to take over and drive the fibrils into supra-fibrillar assemblies. Our findings suggest that the balance between those two types of interaction is not only crucial for the initiation of the self-assembly process but it also controls the morphology and finite size of the supra-fibrillar aggregates giving rise to a rich phase behavior.
Although the role of the erythropoietin (Epo) receptor (EpoR) in erythropoiesis has been known for decades, its role in non-hematopoietic tissues is still not well defined. Klotho has been shown and Epo has been suggested to protect against acute ischemia-reperfusion injury in the kidney. Here we found in rat kidney and in a rat renal tubular epithelial cell line (NRK cells) EpoR transcript and antigen, and EpoR activity signified as Epo-induced phosphorylation of Jak2, ErK, Akt, and Stat5 indicating the presence of functional EpoR. Transgenic overexpression of Klotho or addition of exogenous recombinant Klotho increased kidney EpoR protein and transcript. In NRK cells, Klotho increased EpoR protein, enhanced Epo-triggered phosphorylation of Jak2 and Stat5, the nuclear translocation of phospho-Stat5, and protected NRK cells from hydrogen peroxide cytotoxicity. Knock-down of endogenous EpoR rendered NRK cells more vulnerable, and overexpression of EpoR more resistant to peroxide-induced cytotoxicity, indicating that EpoR mitigates oxidative damage. Knock-down of EpoR by siRNA abolished Epo-induced Jak2, and Stat5 phosphorylation, and blunted the protective effect of Klotho against peroxide-induced cytotoxicity. Thus in the kidney, EpoR and its activity are downstream effectors of Klotho enabling it to function as cytoprotective protein against oxidative injury.
SummaryPrimary familial and congenital polycythemia (PFCP) is an autosomal-dominant proliferative disorder characterized by erythrocytosis and hypersensitivity of erythroid progenitors to erythropoietin (Epo). Several lines of evidence suggest a causal role of truncated erythropoietin receptor (EpoR) in this disease. In this review, we discuss PFCP in the context of erythrocytosis and EpoR signalling. We focus on recent studies describing mechanisms underlying Epo-dependent EpoR down-regulation. One mechanism depends on internalization mediated through the p85 regulatory subunit of the Phosphoinositide 3-Kinase, and the other utilizes ubiquitin-based proteasomal degradation. Truncated PFCP EpoRs are not properly down-regulated upon stimulation, underscoring the importance of these mechanisms in the pathogenesis of PFCP.
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