Two Signals Are Necessary for Cell Proliferation Induced by a Cytokine Receptor gp130: Involvement of STAT3 in Anti-Apoptosis

Fukada, Toshiyuki; Hibi, Masahiko; Yamanaka, Yojiro; Takahashi-Tezuka, Mariko; Fujitani, Yoshio; Yamaguchi, Takuya; Nakajima, Kōichi; Hirano, Toshio

doi:10.1016/s1074-7613(00)80501-4

Cited by 610 publications

(573 citation statements)

References 70 publications

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“…32 In addition, activation of STAT3 was shown to be required for both cell survival and the G1 to S phase cell cycle transition in Ba/F3 cells using pathway-specific deficient gp130 mutants, a common receptor for the IL-6 family of cytokines. 33,34 Consistently, in the present study we showed that by ectopically expressing the human IL-24 receptor in Ba/F3 cells, both rat and human IL-24 could replace IL-3 in supporting the cell survival and proliferation. Although future studies are required to determine the role of deregulation of IL-24 signaling in cancer, the realization of conserved cytokine functions and regulations of IL-24 across species will serve as a solid biochemical foundation for such endeavors.…”

Section: Discussionsupporting

confidence: 87%

Conservation of the genomic structure and receptor-mediated signaling between human and rat IL-24

et al. 2004

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IL-24/MDA-7 is a new member of the IL-10 family of cytokines, which signals through two heterodimeric receptor complexes (IL-20R1/IL-20R2 and IL-22R/IL-20R2). Previously, we identified a rat gene named mob-5, which encodes a secreted protein that shares a high degree of homology with human IL-24. Expression of mob-5 and its putative cell surface receptors was shown to be upregulated by oncogenic ras. Here we show that not only do rat mob-5 and human IL-24 share a strikingly similar genomic structure but also that the rat MOB-5 protein can bind to and signal through the human IL-24 receptors. Like human IL-24, binding of the rat MOB-5 protein to the human IL-24 receptors leads to activation of the JAK/STAT pathway, which in turn supports receptor-dependent survival and proliferation of Ba/F3 cells. Furthermore, using human colon cancer cell lines with somatic knockout of either the mutant or the wild-type k-ras allele, we demonstrate that the human IL-24 receptors also are upregulated by oncogenic ras. Taken together, these results provide strong experimental evidence that MOB-5 is indeed the rat homolog of human IL-24.

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Section: Discussionsupporting

confidence: 87%

Conservation of the genomic structure and receptor-mediated signaling between human and rat IL-24

et al. 2004

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“…As STAT3 has been shown to regulate mitogenesis or/and prevention of cell apoptosis in various cell types (Fukada et al, 1996;Chaturvedi et al, 1998) and 85 kDa STAT3D proteins are overexpressed in a i2 -G204A and a i2 -G204A/v-fms cells, we investigated whether excessive STAT3D expression inhibits NIH3T3 cell proliferation. Cells stably transfected with STAT3D55C cDNA showed increased expression of 85 kDa STAT3D (Figure 8), but also, as observed previously (Kim and Baumann, 1997), a slightly decreased expression of 89 kDa STAT3.…”

Section: Resultsmentioning

confidence: 99%

Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via Src-kinase and STAT3

1999

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We previously showed that G i2 proteins interfere with the transduction of CSF-1 receptor (CSF-1R) proliferation signals (Corre and Hermouet, 1995). To identify CSF-1R pathways controlled by G i2 , we transfected v-fms, the oncogenic equivalent of CSF-1R, in NIH3T3 cells in which G i2 proteins were inactivated by stably expressing a dominant negative mutant form of the a subunit of G i2 (a i2 -G204A). Expression of a i2 -G204A resulted in decreased Src-kinase activity, delayed activation of p42 ERK-MAPK, decreased cyclin D1 expression and reduced proliferation in response to serum. In a i2 -G204A cells transfected with v-fms, Src-kinase activity remained de®cient but p42 MAPK activity and cyclin D1 expression were similar to those of vector/v-fms cells, suggesting that v-fms bypasses Src to activate the ERK-MAPK cascade. However, DNA synthesis and focus formation were inhibited by up to 80% in a i2 -G204A/vfms cells compared to vector/v-fms cells. We found that tyrosine phosphorylation of STAT3, also activated by CSF-1R/v-fms, was inhibited in a i2 -G204A/v-fms cells; in addition, expression of an 85 kDa, C-terminal truncated form of STAT3 (STAT3D) was constitutively increased. Both the inhibition of v-fms-induced STAT3 tyrosine phosphorylation and the increased expression of STAT3D were reproduced by transfecting a dominant negative mutant of Src. Last, we show that expression of STAT3D55C, a mutant form of STAT3 lacking the last 55 C-terminal amino acids, is su cient to inhibit DNA synthesis and v-fms-induced transformation in NIH3T3 cells. In summary, adequate regulation by G i2 proteins of the activity of both Src-kinase and STAT3 is required for optimal cell proliferation in response to CSF-1R/vfms.

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“…The main actions of G-CSF are mediated via binding to a G-CSF receptor, present on hematopoietic, neuronal and glial cells (Schabitz et al, 2003). Once activated, the G-CSF receptor can activate proteins such as STAT3 (Shuai, 2000), which in turn activate antiapoptotic proteins such as bcl-2 (Fukada et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

G-CSF Reduces Infarct Volume and Improves Functional Outcome after Transient Focal Cerebral Ischemia in Mice

Gibson

Bath

Murphy

2005

J Cereb Blood Flow Metab

155

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Growth factors possess neuroprotective and neurotrophic properties in vitro, but few have been extensively studied in vivo after stroke. In the present study, we investigated the potential functional benefits of granulocyte colony-stimulating factor (G-CSF) administration after focal cerebral ischemia. Male mice underwent 60-minute middle cerebral artery occlusion (MCAO) and received G-CSF (50 lg/kg, subcutaneously) or vehicle (saline) at the onset of reperfusion. Granulocyte colony-stimulating factor-treated mice killed at 48 hours after MCAO revealed a 445% reduction (Po0.05) in lesion volume. In terms of body weight recovery, and in tests of motor (grid test and rotarod) and cognitive ability (water maze), MCAO significantly worsened the outcome in vehicletreated mice as compared with shams (Po0.05). However, G-CSF treatment was beneficial as, compared with vehicle, this significantly improved weight recovery and motor ability. This effect was most apparent on the water maze where G-CSF-treated mice were indistinguishable from shams in terms of acquiring the task. These results indicate long-term beneficial effects of a single dose of G-CSF administered on reperfusion, and illustrate the need to further investigate the mechanisms of G-CSF action.

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Two Signals Are Necessary for Cell Proliferation Induced by a Cytokine Receptor gp130: Involvement of STAT3 in Anti-Apoptosis

Cited by 610 publications

References 70 publications

Conservation of the genomic structure and receptor-mediated signaling between human and rat IL-24

Conservation of the genomic structure and receptor-mediated signaling between human and rat IL-24

Regulation by Gi2 proteins of v-fms-induced proliferation and transformation via Src-kinase and STAT3

G-CSF Reduces Infarct Volume and Improves Functional Outcome after Transient Focal Cerebral Ischemia in Mice

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