Aberrant hematopoiesis in mice with inactivation of the gene encoding SOCS-1

Metcalf, Donald; Ws, Alexander; Elefanty, Andrew G.; Nicola, Nicos A.; Hilton, Doug; Starr, Robyn; Mifsud, Sandra; Rago, Ladina Di

doi:10.1038/sj.leu.2401440

Cited by 69 publications

(61 citation statements)

References 18 publications

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“…STAT1 activation was also prolonged in SOCS-1 Ϫ/Ϫ hepatocytes treated with IFN-␥ in vitro. Furthermore, in some cells of the hematopoietic lineage, SOCS-1 deficiency has been shown to result in hypersensitivity to IFN-␥ (39,44). Consistent with studies in other cell types, we found that overexpression of SOCS-1 suppressed responses to IFN-␥ in NIT-1 insulinoma cells, such as IFN-␥-induced STAT1 activation, class I MHC upregulation, and cell death.…”

Section: Discussionsupporting

confidence: 90%

γ-Interferon Signaling in Pancreatic β-Cells Is Persistent but Can Be Terminated by Overexpression of Suppressor of Cytokine Signaling-1

2001

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Section: Discussionsupporting

confidence: 90%

γ-Interferon Signaling in Pancreatic β-Cells Is Persistent but Can Be Terminated by Overexpression of Suppressor of Cytokine Signaling-1

2001

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“…Mice lacking SOCS-1 display erythroid defects, including a subnormal hematocrit and an accumulation of immature red blood cells Metcalf et al, 1999). Data presented here indicate that the erythroid abnormalities in SOCS-1À/À mice may be due, in part, to the increased sensitivity of red cell progenitors to Epo (Figure 7).…”

Section: Discussionmentioning

confidence: 65%

“…They are either induced by Epo (Yoshimura et al, 1995;Starr et al, 1997;Pircher et al, 2001) or expressed in fetal liver (Starr et al, 1997;Marine et al, 1999). While CIS À/À mice have no detectable phenotype (Marine et al, 1999), SOCS-1À/À mice suffer from mild anemia and an excess of nucleated erythroid cells in the spleen Metcalf et al, 1999). It has been reported that SOCS-3 is essential for fetal liver erythropoiesis (Marine et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of SOCS genes in normal and transformed erythroid cells

et al. 2003

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The SOCS family of genes are negative regulators of cytokine signalling with SOCS-1 displaying tumor suppressor activity. SOCS-1, CIS and SOCS-3 have been implicated in the regulation of red blood cell production. In this study, a detailed examination was conducted on the expression patterns of these three SOCS family members in normal erythroid progenitors and a panel of erythroleukemic cell lines. Unexpectedly, differences in SOCS gene expression were observed during maturation of normal red cell progenitors, viz changes to CIS were inversely related to the alterations of SOCS-1 and SOCS-3. Similarly, these SOCS genes were differentially expressed in transformed erythoid cellserythroleukemic cells immortalized at an immature stage of differentiation expressed SOCS-1 and SOCS-3 mRNA constitutively, whereas in more mature cell lines SOCS-1 and CIS were induced only after exposure to erythropoietin (Epo). Significantly, when ectopic expression of the tyrosine kinase Lyn was used to promote differentiation of immature cell lines, constitutive expression of SOCS-1 and SOCS-3 was completely suppressed. Modulation of intracellular signalling via mutated Epo receptors in mature erythroleukemic lines also highlighted different responses by the three SOCS family members. Close scrutiny of SOCS-1 revealed that, despite large increases in mRNA levels, the activity of the promoter did not alter after erythropoietin stimulation; in addition, erythroid cells from SOCS-1À/À mice displayed increased sensitivity to Epo. These observations indicate complex, stagespecific regulation of SOCS genes during normal erythroid maturation and in erythroleukemic cells.

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“…SOCS2 and SOCS3 knockout mice are lethal, whereas SOCS2 knockout mice are 30% larger than their wild-type counterparts. [182][183][184][185] There are other mechanisms to downregulate Jak/STAT signaling. Protein phosphatases, including CD45 and protein tyrosine phosphatase-e C (PTPeC), are also implicated in the negative regulation of Jak/STAT signaling.…”

Section: Overview Of Jak/stat Pathwaymentioning

confidence: 99%

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

et al. 2008

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Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 ( PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia

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Aberrant hematopoiesis in mice with inactivation of the gene encoding SOCS-1

Cited by 69 publications

References 18 publications

γ-Interferon Signaling in Pancreatic β-Cells Is Persistent but Can Be Terminated by Overexpression of Suppressor of Cytokine Signaling-1

γ-Interferon Signaling in Pancreatic β-Cells Is Persistent but Can Be Terminated by Overexpression of Suppressor of Cytokine Signaling-1

Differential regulation of SOCS genes in normal and transformed erythroid cells

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

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