Stat5 Is Essential for the Myelo- and Lymphoproliferative Disease Induced by TEL/JAK2

Schwaller, Juerg; Parganas, Evan; Wang, Demin; Cain, Danielle; Aster, Jon C.; Williams, Ifor R.; Lee, Chien‐Kuo; Gerthner, Rachel; Kitamura, Toshio; Frantsve, Julie; Anastasiadou, Ema; Loh, Mignon L.; Levy, David E.; Ihle, James N.; Gilliland, D. Gary

doi:10.1016/s1097-2765(00)00067-8

Cited by 283 publications

(227 citation statements)

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“…Ectopic expression of SOCS-1 blocks the constitutive tyrosine phosphorylation of TEL-JAK2 and hence its capacity to phosphorylate downstream targets such as STAT1 and STAT5 necessary for cellular transformation (Schwaller et al, 2000). In addition to functioning as a pseudosubstrate inhibitor of TEL-JAK2, we observed that its steady state expression levels of TEL-JAK were markedly decreased in the presence of SOCS-1.…”

Section: Discussionmentioning

confidence: 70%

The tumor suppressor activity of SOCS-1

et al. 2002

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SOCS-1 is an inducible SH2-containing inhibitor of Jak kinases and as such can potently suppress cytokine signaling. SOCS-1 de®cient mice die within the ®rst three weeks of life from a myeloproliferative disorder driven by excessive interferon signaling. We report here that SOCS-1 inhibits proliferation signals induced by a variety of oncogenes active within the hematopoietic system. Ectopic expression of SOCS-1 abolished proliferation mediated by a constitutively active form of the KIT receptor, TEL-JAK2, and v-ABL, and reduced metastasis from BCR-ABL transformed cells. SOCS-1, however, did not interfere with v-SRC or RASV12 mediated cellular transformation. A mutant form of SOCS-1 unable to bind through its SH2 domain to tyrosine phosphorylated proteins could still inhibit KIT, but not TEL-JAK2, indicating multiple mechanisms for SOCS-1-mediated tumor suppression. We show that the steady state levels of TEL-JAK2 and to a greater extent v-ABL are diminished in the presence of SOCS-1. Lastly, we show that SOCS-1 7/7 ®broblasts are more sensitive than wild type ®broblasts to either spontaneous or oncogene-induced transformation. These data suggest that loss-of-function of SOCS-1 may collaborate with a variety of hematopoietic oncogenes to facilitate tumor progression.

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Section: Discussionmentioning

confidence: 70%

The tumor suppressor activity of SOCS-1

et al. 2002

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“…STAT5A1*6 was not used owing to its too strong oncogenic potential in vivo as reported earlier. 36 The transduction efficiencies of NRAS G12V , STAT5A#2 and MLL-ENL were 30-50, 20-40 and 5-10%, respectively, as determined by GFP expression (data not shown).…”

Section: Activation Of Ras-mapk Cascade Enables Hf6 Cells To Grow Witmentioning

confidence: 92%

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

et al. 2009

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Mixed-lineage-leukemia (MLL) fusion oncogenes are closely involved in infant acute leukemia, which is frequently accompanied by mutations or overexpression of FMS-like receptor tyrosine kinase 3 (FLT3). Earlier studies have shown that MLL fusion proteins induced acute leukemia together with another mutation, such as an FLT3 mutant, in mouse models. However, little has hitherto been elucidated regarding the molecular mechanism of the cooperativity in leukemogenesis. Using murine model systems of the MLL-fusion-mediated leukemogenesis leading to oncogenic transformation in vitro and acute leukemia in vivo, this study characterized the molecular network in the cooperative leukemogenesis. This research revealed that MLL fusion proteins cooperated with activation of Ras in vivo, which was substitutable for Raf in vitro, synergistically, but not with activation of signal transducer and activator of transcription 5 (STAT5), to induce acute leukemia in vivo as well as oncogenic transformation in vitro. Furthermore, Hoxa9, one of the MLL-targeted critical molecules, and activation of Ras in vivo, which was replaceable with Raf in vitro, were identified as fundamental components sufficient for mimicking MLL-fusion-mediated leukemogenesis. These findings suggest that the molecular crosstalk between aberrant expression of Hox molecule(s) and activated Raf may have a key role in the MLL-fusion-mediated-leukemogenesis, and may thus help develop the novel molecularly targeted therapy against MLL-related leukemia.

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“…35 Murine BMT assays were performed as described previously. 36 In brief, retroviral supernatants were generated by transient cotransfection of 293T cells with the MSCV2.2-Gateway-IRES-GFP-BCR-ABL 37 or FLT3-ITD/51 38 constructs and packaging construct using Superfect (QIAGEN). The viral titer was estimated by infecting Ba/F3 cells with serial dilutions of viral supernatant and percentage of GFP-positive cells was determined by flow cytometry 48 hours postinfection.…”

Section: Micementioning

confidence: 99%

p90RSK2 is essential for FLT3-ITD– but dispensable for BCR-ABL–induced myeloid leukemia

Elf¹,

Blevins²,

Jin³

et al. 2011

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IntroductionRSK2 is a Ser/Thr kinase that belongs to a family containing 4 members, RSK1 to 4, all of which are downstream substrates of ERK and play a role in various cellular processes including gene expression, cell cycle, survival, and proliferation. RSK family members share both structural and functional similarities, and are uniquely characterized by the presence of 2 distinct kinase domains, both of which are catalytically functional 1-3 (reviewed in Blenis, 4 Frodin and Gammeltoft, 5 and Anjum and Blenis 6 ). The carboxyl-terminal kinase (CTK) domain is responsible for autophosphorylation at Ser386 (numbering based on the murine RSK2 amino acid sequence), which is critical for RSK activation, while the N-terminal kinase (NTK) domain phosphorylates RSK substrates. 2 We recently reported that tyrosine phosphorylation of RSK2 facilitates inactive ERK binding to RSK2 in the initial activation step, and disrupts an autoinhibitory region of RSK2 to achieve full activation. [7][8][9] RSK2 phosphorylates multiple signaling effectors that possess RRXS/T or RXRXXS/T motifs. 10 These RSK2 phosphorylation targets include transcriptional regulators such as cAMP-response element-binding protein (CREB), 11 c-Fos, 12,13 NFATc4, 14 NFAT3, 15 ATF4, 16 and Nur77. 17 Phosphorylation and activation of these transcription factors are important for regulation of gene expression. RSK2 also phosphorylates histone H3, which contributes to chromatin remodeling during mitosis and transcriptional activation. 18 In addition, RSK2 promotes cell survival by phosphorylating and inhibiting proapoptotic protein factors including BAD,19 Bim, 20 and death-associated protein kinase (DAPK). 21 Moreover, RSK2 promotes proliferation by phosphorylating GSK3␤, 22 NHE-1, 23 and p27 kip1 . 24 Therefore, RSK2 may serve as a key regulator by activating multiple signaling effectors in a signaling network that promotes cell survival and proliferation.Defects in the human RSK2 gene are associated with CoffinLowry syndrome (CLS), an X-linked mental retardation. 25,26 Although there is no evidence that RSK2 is mutated in human cancers, RSK2 signaling has been demonstrated to play a key role in the pathogenesis and disease progression of some human malignancies, including metastatic head and neck cancer, 27 FGFR1-expressing prostate cancer, 28,29 and osteosarcoma. 16,30 We recently found that oncogenic FGFR3 phosphorylates and activates RSK2 to induce hematopoietic transformation. 7,9 Targeting RSK2 but not RSK1 by siRNA or treatment with a specific RSK inhibitor fmk 31,32 effectively induced apoptosis in FGFR3-expressing human t(4;14)-positive myeloma cells and primary patient myeloma cells. These findings suggest a critical role for RSK2 in FGFR3-induced hematopoietic transformation.In this report, we focus on the role of RSK2 in other hematopoietic malignancies induced by different leukemogenic tyrosine kinases (LTKs) including BCR-ABL and FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutant. BCR-ABL is a constitutively active fus...

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Stat5 Is Essential for the Myelo- and Lymphoproliferative Disease Induced by TEL/JAK2

Cited by 283 publications

References 53 publications

The tumor suppressor activity of SOCS-1

The tumor suppressor activity of SOCS-1

Mixed-lineage-leukemia (MLL) fusion protein collaborates with Ras to induce acute leukemia through aberrant Hox expression and Raf activation

p90RSK2 is essential for FLT3-ITD– but dispensable for BCR-ABL–induced myeloid leukemia

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