A Permissive Role for Phosphatidylinositol 3-Kinase in the Stat5- mediated Expression of Cyclin D2 by the Interleukin-2 Receptor

Moon, James J.; Rubio, Eric D.; Martino, Anthony; Krumm, Anton; Nelson, Brad H.

doi:10.1074/jbc.m308998200

Cited by 54 publications

(43 citation statements)

References 52 publications

(66 reference statements)

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“…It is also possible that STAT5 activation is relatively similar between KLRG1 hi and KLRG1 lo effector CD8 T cells during the contraction phase in vivo but that differential expression of other transcription factors or microRNAs modulates STAT5-dependent gene expression, leading to differential gene expression and cell survival. Finally, in a T-cell line, it has been shown that STAT5 cannot act alone, and requires PI3K/AKT signaling, to activate ccnd2 (CYCLIN D2) and bcl2l1 (BCLXL) transcription (45). Thus, KLRG1 hi cells would be unable to activate genes requiring both STAT5 and PI3K/AKT activity.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Hand

Cui²,

Jung³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

191

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During viral infection, effector CD8 T cells contract to form a population of protective memory cells that is maintained by IL-7 and IL-15. The mechanisms that control effector cell death during infection are poorly understood. We investigated how short-and long-lived antiviral CD8 T cells differentially used the survival and cell growth pathways PI3K/AKT and JAK/STAT5. In response to IL-15, long-lived memory precursor cells activated AKT significantly better than shortlived effector cells. However, constitutive AKT activation did not enhance memory CD8 T-cell survival but rather repressed IL-7 and IL-15 receptor expression, STAT5 phosphorylation, and BCL2 expression. Conversely, constitutive STAT5 activation profoundly enhanced effector and memory CD8 T-cell survival and augmented homeostatic proliferation, AKT activation, and BCL2 expression. Taken together, these data illustrate that effector and memory cell viability depends on properly balanced PI3K/AKT signaling and the maintenance of STAT5 signaling.apoptosis | cytokine signaling | interleukin 15 | interleukin 7 | lymphocytic choriomeningitis virus M emory CD8 T cells form from a much larger effector population and provide long-term immunity against subsequent infections via rapid reactivation. The exact biochemical mechanism governing the survival of memory cells and apoptosis of the majority of effector cells is not well understood (1). As naïve T cells differentiate into effector and memory T cells, cytokines play a key role in their differentiation and survival. IL-2, IL-7, and IL-15 promote the expansion and survival of activated T cells (2). As memory CD8 T cells form following acute viral infection, two of these cytokines, IL-15 and IL-7, direct memory T cell survival and homeostasis (3, 4). Downstream of their specific receptors, IL-7 and IL-15 activate two primary pathways: janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) and phosphoinositide 3-kinase (PI3K)/AK-transforming (AKT). Activation of these two pathways results in decreased levels of proapoptotic proteins, increased expression of antiapoptotic genes such as BCL2, and activation of cellular growth and proliferation pathways regulated by mTOR and cyclins (5). The balance between these pro-and antiapoptotic factors controls the survival of CD8 T cells after immunization (6).Early models predicted that effector CD8 T-cell contraction was a result of deprivation of T-cell growth factor cytokines that wane during the later stages of infection and that survival was determined via the stochastic interaction of effector T cells with these cytokines. However, effector CD8 T cells are a heterogeneous population composed of cells with varying intrinsic potential for survival and differentiation into memory cells (3,7,8). During several types of infections [such as lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), Listeria monocytogenes, and Toxoplasma gondii], most of the effector CD8 T cells terminally differentiate and become short-lived, but ...

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Section: Discussionmentioning

confidence: 99%

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Hand

Cui²,

Jung³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

191

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“…Differentiation was induced by addition of dimethyl sulfoxide (Me 2 SO) for 2 h at a final concentration of 1.5%. The IL-2-dependent CTLL-2 cell line was grown and induced as described (14).…”

Section: Methodsmentioning

confidence: 99%

Transcription-induced Chromatin Remodeling at the c-myc Gene Involves the Local Exchange of Histone H2A.Z

Farris

Rubio

Moon

et al. 2005

Journal of Biological Chemistry

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The post-translational modification of histones and the incorporation of core histone variants play key roles in governing gene expression. Many eukaryotic genes regulate their expression by limiting the escape of RNA polymerase from promoter-proximal pause sites. Here we report that elongating RNA polymerase II complexes encounter distinct chromatin landscapes that are marked by methylation of lysine residues Lys 4 , Lys 79 , and Lys 36 of histone H3. However, neither histone methylation nor acetylation directly regulates the release of elongation complexes stalled at promoter-proximal pause sites of the c-myc gene. In contrast, transcriptional activation is associated with local displacement of the histone variant H2A.Z within the transcribed region and incorporation of the major histone variant H2A. This result indicates that transcribing RNA polymerase II remodels chromatin in part through coincident displacement of H2A.Z-H2B dimers and incorporation of H2A-H2B dimers. In combination, these results suggest a new model in which the incorporation of H2A.Z into nucleosomes down-regulates transcription; at the same time it may act as a cellular memory for transcriptionally poised gene domains. RNA pol II1 encounters nucleosomes and other multiprotein complexes during transcription. Conceptually, any mechanism that destabilizes the DNA-histone interaction or removes part or all of the histone octamer potentially increases the elongation efficiency of RNA polymerases. Protein complexes such as FACT, Elongator, and Swi/Snf have been proposed to alleviate barriers that are imposed by chromatin (1-3). For instance, the protein complex FACT assists RNA polymerase during elongation by altering the nucleosomal conformation and destabilizing the interaction between the H2A/H2B dimer and the (H3/H4) 2 tetramer (4). After the transcription complex has passed the nucleosome, FACT participates in the reassembly of the nucleosome. In addition to the FACT-mediated catalytic remodeling of nucleosomes, the post-translational modification of histones, and/or the incorporation of histone variants also may facilitate the passage of the transcription complex through nucleosomes (5-7). For example, the identification of the acetyltransferase activity in the Elp3 subunit of the RNA pol II-associated Elongator complex suggests that histone acetylation is an important component in the regulation of transcription elongation (8,9). Indeed, previous studies demonstrated that the yeast Elongator complex is associated with nascent transcripts (2). In addition to histone acetylation, methylation of H3 lysine residues Lys -specific histone demethylase LSD1 suggests a model in which RNA polymerase II elongation is regulated by the antagonistic action of histone methyltransferases and histone demethylases (12). Alternatively, a replication-independent histone exchange pathway in which variant forms of histones are incorporated during active transcription may provide an opportunity to continuously exchange histones with either hyper-or hypomethyl...

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“…The cycD2 expression is also upregulated by IL-2 receptor signals and in part accounts for the T-cell proliferation stimulated by IL-2. The IL-2 receptor induces cycD2 by activating transcription factor Stat5, which binds directly to a cognate site in the cyclin D2 promoter (Martino et al, 2001;Moon et al, 2004;Fung et al, 2005). Tax may cooperate with IL-2-signaling either indirectly through stimulating the expression of IL2Ra or directly by activating the cycD2 promoter (Huang et al, 1997;Santiago et al, 1999).…”

Section: Cyclin D Binding and Upregulationmentioning

confidence: 99%

Molecular mechanisms of cellular transformation by HTLV-1 Tax

2005

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A Permissive Role for Phosphatidylinositol 3-Kinase in the Stat5- mediated Expression of Cyclin D2 by the Interleukin-2 Receptor

Cited by 54 publications

References 52 publications

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Transcription-induced Chromatin Remodeling at the c-myc Gene Involves the Local Exchange of Histone H2A.Z

Molecular mechanisms of cellular transformation by HTLV-1 Tax

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