AMP-activated Protein Kinase-regulated Phosphorylation and Acetylation of Importin α1

Wang, Wengong; Yang, Xiaoling; Kawai, Tomoko; Silanes, Isabel López de; Mazan-Mamczarz, Krystyna; Chen, Peili; Chook, Yuh Min; Quensel, Christina; Köhler, M; Gorospe, Myriam

doi:10.1074/jbc.m409014200

Cited by 123 publications

(112 citation statements)

References 75 publications

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“…However, more recent studies demonstrated that the hinge region mediates primarily the nuclear import of HuR by interacting with the transportin-1 or transportin-2 nuclear transport receptor (89,90). It has also been reported that, upon activation of AMP-activated protein kinase, the importin-␣1 adaptor protein can contribute to HuR nuclear import (91). The current model of HuR shuttling in the absence of cellular stress assumes, however, that the nuclear import of HuR is mediated by the interaction of its hinge region with transport factors of the transportin family.…”

Section: Discussionmentioning

confidence: 99%

Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Prechtel

Chemnitz

Schirmer

et al. 2006

Journal of Biological Chemistry

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Dendritic cells (DCs) 3 are the most potent antigen-presenting cells of the immune system and are specialized to sensitize helper and killer T cells during the induction of T cell-mediated immunity (1, 2). In fact, DCs are the only antigen-presenting cells that are able to stimulate naive CD4 ϩ and CD8 ϩ T cells and are therefore referred to as "nature's adjuvant."The CD83 molecule is to date the best known marker for fully mature DCs because CD83 is predominantly expressed on the surface of dendritic lineage cells and cannot be detected on immature DC precursors (3-5). Although its exact function remains to be determined, the fact that CD83 expression is activated during DC maturation, together with co-stimulatory molecules such as CD80 and CD86, suggests a functionally important role for CD83 in DC-mediated T cell immunity (6, 7). This notion is also supported by the fact that inhibition of CD83 expression during DC maturation reduces the T cell stimulatory capacity of these DCs in allo-mixed leukocyte reactions (8). A study using the soluble extracellular domain of CD83 has provided the first direct evidence that this specific surface molecule is indeed functionally important for T cell activation; the soluble CD83 protein completely inhibited DC-mediated T cell stimulation in a concentration-dependent manner in vitro (9). These data were subsequently confirmed in an independent study by using CD83-Ig fusion protein (10). Thus, CD83 appears to play an important functional role in the regulation of DC-mediated T cell-specific immune responses. Therefore, the investigation of the regulation of CD83 expression may provide novel opportunities to modulate DC activity and subsequently DC-mediated immune responses.

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Section: Discussionmentioning

confidence: 99%

Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Prechtel

Chemnitz

Schirmer

et al. 2006

Journal of Biological Chemistry

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“…The regulation of mRNA stability is mediated by the interaction of trans-acting factors (A/ U-binding proteins, AUBPs) with AREs, which are capable of recruiting the mRNA degradation machinery (Wilusz and Wilusz, 2004). Known ARE-binding regulators of mRNA turnover include AUF1 (DeMaria and Brewer, 1996), HuR (Peng et al, 1998), tristetraprolin (TTP) (Blackshear, 2002) and BRF1 (Stoecklin et al, 2002), whose activities have been demonstrated to be regulated by phosphomodulation (Wilson et al, 2003;Chrestensen et al, 2004;Schmidlin et al, 2004;Wang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling

et al. 2006

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The differential expression of the critical cell cycle control proteins cyclin D1 and c-myc has been shown to result in Akt-dependent hypersensitivity of tumor cells to mTOR inhibitors. We have previously demonstrated that the differential utilization of internal ribosome entry sites within the mRNAs of these transcripts allows maintenance of protein synthesis in the face of rapamycin (rapa) exposure in an Akt-dependent manner. Here, we demonstrate that in addition to this mechanism, cyclin D1 and c-myc mRNA stability is also coordinately regulated following rapa treatment depending on Akt activity status. We identify A/U-rich response elements within the 3 0 untranslated regions (UTRs) of these transcripts, which confer the observed differential stabilities and show that the RNA-binding protein, tristetraprolin (TTP), interacts with these elements. We also present evidence that TTP accumulates in response to rapa exposure, binds to the cis-acting elements within the cyclin D1 and c-myc 3 0 UTRs and is differentially serine phosphorylated in an Akt-dependent manner. Furthermore, the differential phosphorylation status of TTP results in its sequestration by 14-3-3 proteins in quiescent Akt-containing cells. Finally, siRNA-mediated knockdown of TTP expression or inhibiting a known regulator of TTP phosphorylation, p38 MAP kinase, abolishes the effects on cyclin D1 and c-myc mRNA stability. We assume that the differential control of cyclin D1 and c-myc mRNA stability and translational efficiency constitutes a coordinate response to rapa contributing to the maintenance of expression of these determinants in rapa-resistant quiescent Aktcontaining cells following exposure.

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“…28 HNS is mainly responsible for nuclear/cytoplasmic shuttling upon binding adaptor proteins for nuclear export such as pp32/PHAP-I and APRIL 29,30 and with import factors transportin-1, -2 and importin a: [31][32][33] Previous Electrophoretic Mobility Shift Assay (EMSA)-based report 34 suggests that the RRM23 linker, together with the RRM3 domain, could also have an additional role in stabilizing HuR-AREs complexes. This enhancement of ARE-binding activity was greater than that observed in Surface Plasmon Resonance (SPR) experiments with HuD, a highly homolog protein to HuR, 35 where the RRM23 linker showed a negligible effect in RNA binding.…”

mentioning

confidence: 99%

The C-terminal RNA binding motif of HuR is a multi-functional domain leading to HuR oligomerization and binding to U-rich RNA targets

et al. 2014

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AMP-activated Protein Kinase-regulated Phosphorylation and Acetylation of Importin α1

Cited by 123 publications

References 75 publications

Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Expression of CD83 Is Regulated by HuR via a Novel cis-Active Coding Region RNA Element

Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling

The C-terminal RNA binding motif of HuR is a multi-functional domain leading to HuR oligomerization and binding to U-rich RNA targets

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