Janus kinases: components of multiple signaling pathways

Rane, Sushil G.; Reddy, E. Premkumar

doi:10.1038/sj.onc.1203925

Cited by 421 publications

(337 citation statements)

References 214 publications

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“…Cytoplasmic Janus protein tyrosine kinases (JAKs) are critical components of multiple signaling pathways that govern survival, proliferation, and apoptosis (reviewed in Rane and Reddy, 2000). The primary substrates for JAK kinases are cytokine receptors which dimerize or oligomerize upon ligand binding, but JAK kinases are also known to activate members of the signal transducers and activators of transcription (STAT) family.…”

Section: Other Signaling Molecules and Pathways Jak/stat Pathwaymentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,094

1,596

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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. Published 2002 Wiley‐Liss, Inc.

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Section: Other Signaling Molecules and Pathways Jak/stat Pathwaymentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,094

1,596

View full text Add to dashboard Cite

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“…If lymphocyte growth and proliferation are allowed to proceed in excess, oncogenesis [1] or autoimmunity can occur [2]. In contrast, if too much apoptosis occurs, degenerative or immunodeficiency disease may arise [3][4][5]. To regulate this balance, tissue-specific growth factors are required to provide cell survival and growth signals [6].…”

Section: Introductionmentioning

confidence: 99%

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

et al. 2003

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The mechanisms that regulate basal T cell size and metabolic activity are uncertain. Since the phosphatidylinositol-3 phosphate kinase (PI3 K) and Akt (PKB) pathway has been shown in model organisms to regulate both cell size and metabolism, we generated transgenic mice expressing a constitutively active form of Akt (myristoylated Akt, mAkt) in T cells. Naive transgenic T cells were enlarged and had increased rates of glycolysis compared to control T cells. In addition, mAkt transgenic T cells resisted death-by-neglect upon in vitro culture. Upon activation, mAkt-transgenic T cells were less dependent than control cells on costimulation through CD28 and could both grow rapidly and secrete cytokines in the absence of CD28 ligation. In addition, transgenic expression of mAkt led to the accumulation of CD4 T cells and B cells with age. Many aged mAkt-transgenic mice also developed autoimmunity with immunoglobulin deposits on kidney glomeruli and displayed increased incidence of lymphoma. Together, these data show that Akt activation is sufficient to increase basal T cell size and metabolism. Enhancement of T cell metabolism by Akt and more rapid CD28-independent T cell growth may contribute to the accumulation of excess immune cells and the development of lymphoma and autoimmunity.

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“…This constitutively active mutant of Stat3 (Stat3-C) has been shown to dimerize spontaneously in the absence of tyrosine phosphorylation, bind to DNA, and activate transcription of target molecules (Bromberg et al, 1999). Stat3 was an attractive candidate to play a role in Jak3 transcription during myeloid differentiation because it is known to be phosphorylated in response to G-CSF (Ihle, 1996;Chakraborty and Tweardy, 1998;Rane and Reddy, 2000), and previous studies have suggested an essential role for Stat3 in granulocytic differentiation (de Koning et al, 2000;McLemore et al, 2001). Figure 4a shows the effect of Stat3 on Jak3 promoter activity in G-CSF-stimulated 32Dcl3 cells.…”

Section: Resultsmentioning

confidence: 99%

“…On average, cotransfection of either constitutively activated Stat3 (Stat3-C) or wildtype Stat3 (WT Stat3) resulted in a three-fold increase in Jak3 promoter activity in these cells. Since WT Stat3 is known to be phosphorylated by G-CSF (Ihle, 1996;Chakraborty and Tweardy, 1998;Rane and Reddy, 2000), it is not surprising that WT Stat3 and Stat3-C would each be able to enhance activity of the Jak3 promoter to a similar extent in G-CSF stimulated cells. The three-fold increase in Jak3 promoter activity in 32Dcl3 cells stimulated with G-CSF correlates with the results of the luciferase assays performed with the À100 Stat mutant construct, which showed that site-specific mutation of the À44 to À53 GAS element in the Jak3 promoter decreased luciferase activity by two-fold in G-CSF-stimulated 32Dcl3 cells.…”

Section: Resultsmentioning

confidence: 99%

“…The three-fold increase in Jak3 promoter activity in 32Dcl3 cells stimulated with G-CSF correlates with the results of the luciferase assays performed with the À100 Stat mutant construct, which showed that site-specific mutation of the À44 to À53 GAS element in the Jak3 promoter decreased luciferase activity by two-fold in G-CSF-stimulated 32Dcl3 cells. Since phosphorylation of Stats is known to take place immediately after binding of cytokines to their receptors (Ihle, 1996;Rane and Reddy, 2000), unstimulated 32Dcl3 cells present the opportunity to test the effects of exogenous activated Stats on cells which no longer can phosphorylate endogenous Stats. The results of cotransfection of Stat3 on Jak3 promoter activity in unstimulated 32Dcl3 cells are shown in Figure 4b.…”

Section: Resultsmentioning

confidence: 99%

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Granulocyte colony-stimulating factor-induced upregulation of Jak3 transcription during granulocytic differentiation is mediated by the cooperative action of Sp1 and Stat3

et al. 2006

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We previously demonstrated that Jak3 is a primary response gene for G-CSF and ectopic overexpression of Jak3 can accelerate granulocytic differentiation of normal mouse bone marrow cells induced by G-CSF and GM-CSF. To gain insight into the regulation of G-CSFinduced transcription of Jak3, we constructed deletion and linker scanning mutants of the Jak3 promoter sequences and performed luciferase reporter assays in the murine myeloid cell line 32Dcl3, with and without G-CSF stimulation. These experiments showed that mutation of a À67 to À85 element, which contained a putative Sp1 binding site, or mutation of a À44 to À53 GAS element resulted in a marked reduction of Jak3 promoter activity. Electrophoretic mobility shift assays revealed that Sp1 and Stat3 present in nuclear lysates of 32Dcl3 cells stimulated with G-CSF can bind to the À67 to À85 element and À44 to À53 GAS element, respectively. In addition, cotransfection of a constitutively active mutant of Stat3 along with a Jak3 promoter/luciferase reporter resulted in enhanced Jak3 promoter activity. Together, these results demonstrate that activation of Jak3 transcription during G-CSF-induced granulocytic differentiation is mediated by the combined action of Sp1 and Stat3, a mechanism also shown to be important in IL-6-induced monocytic differentiation.

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Janus kinases: components of multiple signaling pathways

Cited by 421 publications

References 214 publications

Cellular response to oxidative stress: Signaling for suicide and survival*

Cellular response to oxidative stress: Signaling for suicide and survival*

Activated Akt promotes increased resting T cell size, CD28‐independent T cell growth, and development of autoimmunity and lymphoma

Granulocyte colony-stimulating factor-induced upregulation of Jak3 transcription during granulocytic differentiation is mediated by the cooperative action of Sp1 and Stat3

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