TRAIL regulates normal erythroid maturation through an ERK-dependent pathway

Secchiero, Paola; Melloni, Elisabetta; Heikinheimo, Markku; Mannisto, Susanna; Pietro, Roberta Di; Iacone, A; Zauli, Giorgio

doi:10.1182/blood-2003-06-2137

Cited by 110 publications

(97 citation statements)

References 34 publications

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“…Taxane-induced microtubule damage also triggers signaling cascades that involve Erk1/2 (30, 31). Erk1/2 acts both upstream and downstream of TRAIL-R; therefore, it is also possible that activation of Erk1/2 occurs as a downstream effect of up-regulation of the TRAIL-R (17,18). Although p53 is known to induce the death receptors, it is unlikely that this mechanism is operative here as p53 up-regulation of these receptors occurs at the transcriptional level (19), and our experiments showed that paclitaxel induced TRAIL-R via a posttranscriptional mechanism (because mRNA levels were not increased).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies

Gong

Yang²,

Kohanim³

et al. 2006

Molecular Cancer Therapeutics

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Susceptibility to apoptosis by tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) is mediated through cognate death receptor signaling. We hypothesized that auto-amplification of this apparatus would enhance antitumor effects in vivo and could be optimized using the results obtained from novel imaging techniques. We therefore imaged mice bearing human colorectal cancer (Colo205) tumor xenografts with HGS-ETR1 and HGS-ETR2 agonist antibodies to TRAIL receptor-1 (TRAIL-R1) and TRAIL-R2, respectively, after radiolabeling the antibodies. Paclitaxel significantly increased in vivo expression of TRAIL-R1 and TRAIL-R2 in a time-dependent manner. The imaging results were confirmed by immunoblots for steady-state protein levels (>20-fold increase in TRAIL-R1 and TRAIL-R2 levels in tumor xenografts by 48 h after paclitaxel administration). TRAIL-R1 and TRAIL-R2 mRNA expression did not change, suggesting that these effects were posttranscriptional. Sequential treatment with paclitaxel followed by HGS-ETR1 or HGS-ETR2 after 48 h resulted in markedly enhanced antitumor activity against Colo205 mouse xenografts. Our experiments suggest that sequential taxane treatment followed by TRAIL-R agonist antibodies could be applied in the clinic, and that novel imaging techniques using radiolabeled receptor antibodies may be exploitable to optimize sequence timing and patient selection.

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Section: Discussionmentioning

confidence: 99%

“…11). Erk1/2 acts both upstream and downstream of TRAIL-R (17,18). In addition, it has been reported that TRAIL-R2 is a DNA damage -inducible, p53-regulated death receptor gene (19).…”

Section: Paclitaxel Enhances Tumor Uptake Of 99m Tc-ecl Abeled Trail-mentioning

confidence: 99%

Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies

Gong

Yang²,

Kohanim³

et al. 2006

Molecular Cancer Therapeutics

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“…Developing erythroid cells express CD95 and TRAIL receptors (5,36). To investigate whether IFN-␥ may inhibit erythropoiesis through different effectors, we analyzed the expression of members of the TNF/TNFR family, including TRAIL and the recently characterized proteins TWEAK and TL1A, in IFN-␥-treated erythroid precursor cells.…”

Section: Ifn-␥ Up-regulates Multiple Tnf Family Members On Immature Ementioning

confidence: 99%

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

Felli

Pedini

Zeuner

et al. 2005

The Journal of Immunology

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IFN-γ inhibits the growth and differentiation of erythroid precursor cells and mediates hemopoietic suppression through mechanisms that are not completely understood. We found that treatment of human erythroid precursor cells with IFN-γ up-regulates the expression of multiple members of the TNF family, including TRAIL and the recently characterized protein TWEAK. TWEAK and its receptor fibroblast growth factor-inducible 14 (Fn14) were expressed by purified erythroblasts at all the stages of maturation. Exposure to recombinant TWEAK or agonist anti-Fn14 Abs was able to inhibit erythroid cell growth and differentiation through caspase activation. Because other members of the TNF family such as TRAIL and CD95 ligand (CD95L) are known to interfere with erythroblast growth and differentiation, we investigated the role of different TNF/TNFR family proteins as potential effectors of IFN-γ in the immature hemopoietic compartment. Treatment of erythroid precursor cells with agents that blocked either TRAIL, CD95L, or TWEAK activity was partially able to revert the effect of IFN-γ on erythroid proliferation and differentiation. However, the simultaneous inhibition of TRAIL, TWEAK, and CD95L resulted in a complete abrogation of IFN-γ inhibitory effects, indicating the requirement of different receptor-mediated signals in IFN-γ-mediated hemopoietic suppression. These results establish a new role for TWEAK and its receptor in normal and IFN-γ-mediated regulation of hematopoiesis and show that the effects of IFN-γ on immature erythroid cells depend on multiple interactions between TNF family members and their receptors.

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“…[2][3][4] The ligand and its receptors are expressed at low levels in human hematopoietic progenitors under steady-state conditions; therefore, these cells are largely unaffected by this signaling pathway. [17][18][19] Among the known five TRAIL receptors, DR4 (TRAIL-R1) and DR5 (TRAIL-R2) are associated with transduction of apoptotic signals in humans, 16 whereas mice express only TRAIL-R2. 20,21 Although mRNA encoding TRAIL receptors DR4 and DR5 is frequently detected in CD34 þ progenitors, these cells were insensitive to apoptosis 22,23 even in the presence of low doses of doxorubicin.…”

Section: Introductionmentioning

confidence: 99%

“…23,28,29 Therefore, TRAIL may serve as a negative regulator of expanding clones in the distal stages of differentiation of all hematopoietic lineages. 13,[17][18][19]30,31 As umbilical cord blood (UCB) becomes an important source of hematopoietic progenitors for transplantation, we evaluated the effect of TRAIL in proximal stages of their activity. We recently showed that the Fas/Fas-ligand interaction transduces trophic signals in early stages of hematopoietic cell engraftment, 32 because the most primitive progenitors are insensitive to Fas-mediated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation

et al. 2010

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The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway has selective toxicity to malignant cells. The TRAIL receptors DR4 and DR5 are expressed at low levels in human umbilical cord blood cells (3-15%) and are upregulated by incubation with the cognate ligand, triggering apoptosis in 70-80% of receptor-positive cells (Po0.001). Apoptosis is not induced in hematopoietic progenitors, as determined from sustained severe combined immunodeficiency reconstituting potential and clonogenic activity. Furthermore, elimination of dead cells after incubation with TRAIL for 72 h results in a threefold enrichment in myeloid progenitors. Exposure to TRAIL in semisolid cultures showed synergistic activity of DR4 and granulocyte/macrophage colony-stimulating factor in recruiting lineage-negative (lin À ) and CD34 þ progenitors and in promoting the formation of large colonies. In murine bone marrow, B30% of lin À cells express TRAIL-R2 (the only murine receptor), and the receptor is upregulated after transplantation in cycling and differentiating donor cells that home to the host marrow. However, this receptor is almost ubiquitously expressed in the most primitive (lin À SCA-1 þ c-kit þ ) progenitors, and stimulates the clonogenic activity of lin À cells (Po0.001), suggesting a tropic function after transplantation. It is concluded that TRAIL does not trigger apoptosis in hematopoietic progenitors, and upregulation of its cognate receptors under stress conditions mediates tropic signaling that supports recovery from hypoplasia.

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TRAIL regulates normal erythroid maturation through an ERK-dependent pathway

Abstract: In order to investigate the biologic activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on human erythropoiesis, glycophorin A (GPA) ؉ erythroid cells were generated in serum-free liquid phase from human cord blood (CB) CD34 ؉

Cited by 110 publications

References 34 publications

Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies

Novel in vivo imaging shows up-regulation of death receptors by paclitaxel and correlates with enhanced antitumor effects of receptor agonist antibodies

Multiple Members of the TNF Superfamily Contribute to IFN-γ-Mediated Inhibition of Erythropoiesis

Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation

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