Nuclear Translocation and DNA Recognition Signals Colocalized within the bZIP Domain of Cyclic Adenosine 3′,5′-Monophosphate Response Element-Binding Protein CREB

Waeber, Gérard; Habener, Joel F.

doi:10.1210/mend-5-10-1431

Cited by 62 publications

(36 citation statements)

References 38 publications

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“…Since CREB contains a NLS that mediates its nuclear localisation 26 , axonal CREB may be retrogradely transported to the cell body. To determine if endogenouslyexpressed CREB is retrogradely trafficked, we examined the time course of CREB reduction in axons upon replacement of media with NGF-free media.…”

Section: Locally Synthesised Creb Is Retrogradely Trafficked To the Nmentioning

confidence: 99%

Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

et al. 2008

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During development of the nervous system, axons and growth cones contain mRNAs, such as β-actin, cofilin, and RhoA, that are locally translated in response to guidance cues. Intra-axonal translation of these mRNAs results in local morphological responses, however other functions of intra-axonal mRNA translation remain unknown. Here we show that axons of developing mammalian neurons contain mRNA encoding the cAMP-responsive element (CRE)-binding protein (CREB). CREB is translated within axons in response to NGF and is retrogradely trafficked to the cell body. In neurons that are selectively deficient in axonal CREB transcripts, increases in nuclear pCREB, CRE-mediated transcription, and neuronal survival elicited by axonal application of NGF are abolished, indicating a signalling function for axonally-synthesised CREB. These studies identify a signalling role for axonally-derived CREB, and indicate that signaldependent synthesis and retrograde trafficking of transcription factors enables specific transcriptional responses to signalling events at distal axons.An important mechanism by which the protein composition at specific subcellular sites is regulated is by the precise intracellular targeting and translation of certain mRNAs 1 . This mechanism particularly evident in axons of developing neurons, which contain mRNAs, ribosomes, and other translational machinery 2 . Most known axonal mRNAs encode proteins that are involved in cytoskeletal regulation, and are involved in mediating the response to guidance cues [3][4][5] . Roles for axonal mRNA translation in other processes have not been established.One critical function of axons during development is to detect signals in the extracellular environment and to transduce these signals into changes in gene expression in the nucleus [6][7][8][9] . In developing sympathetic and sensory axons, growth cones detect nerve growth factor (NGF) synthesised by target cells, resulting in the generation of a retrograde signal that is conveyed to the soma that promotes neuronal survival 10 .Here we describe a role for axonal mRNA translation in the regulation of neuronal survival and nuclear transcription elicited by axonal application of NGF. We find NGF triggers axonal protein synthesis, which is required for NGF-mediated retrograde survival. A cDNA library prepared from the axons of developing sensory neurons reveals that CREB mRNA is an axonally-localised transcript. We find that CREB is selectively translated in axons in response to NGF and retrogradely trafficked to the cell body. Furthermore, selective 3 Correspondence should be addressed to S.R.J. (srj2003@med.cornell.edu). NIH Public Access Author ManuscriptNat Cell Biol. Author manuscript; available in PMC 2011 August 9. knockdown of axonal CREB mRNA reveals that axonally-synthesised CREB is required for NGF at axons to promote the accumulation of pCREB in the nucleus, transcription of a CRE-containing reporter gene, and neuronal survival. These data identify a role for axonally-synthesised CREB and identify a ...

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Section: Locally Synthesised Creb Is Retrogradely Trafficked To the Nmentioning

confidence: 99%

Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

et al. 2008

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“…Although nuclear localization and DNA binding are functionally separable, NLS are observed in the DNA binding domains of other classes of transcription factors, including POU homeodomains (Sock et al, 1996) and HMG box (Poulat et al, 1995), HLH (Tapscott et al, 1988), and bZip proteins (Waeber and Habener, 1991). These observations indicate that the B motif is a multifunctional domain of type-B ARRs.…”

Section: Discussionmentioning

confidence: 99%

Molecular Structure of the GARP Family of Plant Myb-Related DNA Binding Motifs of the Arabidopsis Response Regulators

et al. 2002

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The B motif is a signature of type-B response regulators (ARRs) involved in His-to-Asp phosphorelay signal transduction systems in Arabidopsis. Homologous motifs occur widely in the GARP family of plant transcription factors. To gain general insight into the structure and function of B motifs (or GARP motifs), we characterized the B motif derived from a representative ARR, ARR10, which led to a number of intriguing findings. First, the B motif of ARR10 (named ARR10-B and extending from Thr-179 to Ser-242) possesses a nuclear localization signal, as indicated by the intracellular localization of a green fluorescent protein-ARR10-B fusion protein in onion epidermal cells. Second, the purified ARR10-B molecule binds specifically in vitro to DNA with the core sequence AGATT. This was demonstrated by several in vitro approaches, including PCR-assisted DNA binding site selection, gel retardation assays, and surface plasmon resonance analysis. Finally, the three-dimensional structure of ARR10-B in solution was determined by NMR spectroscopy, showing that it contains a helix-turn-helix structure. Furthermore, the mode of interaction between ARR10-B and the target DNA was assessed extensively by NMR spectroscopy. Together, these results lead us to propose that the mechanism of DNA recognition by ARR10-B is essentially the same as that of homeodomains. We conclude that the B motif is a multifunctional domain responsible for both nuclear localization and DNA binding and suggest that these insights could be applicable generally to the large GARP family of plant transcription factors.

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“…The activation of CRE-containing promoters by phosphorylation of CREB requires that the kinase have access to CREB, which is localized in the nucleus (53). CaMKIV has been shown previously to be localized to the nucleus by electron microscopy (21) (38).…”

Section: Discussionmentioning

confidence: 99%

Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression.

et al. 1994

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Phosphorylation of CREB (cyclic AMP [cAMP]- response element [CRE]-binding protein) by cAMP-dependent protein kinase (PKA) leads to the activation of many promoters containing CREs. In neurons and other cell types, CREB phosphorylation and activation of CRE-containing promoters can occur in response to elevated intracellular Ca2+. In cultured cells that normally lack this Ca2+ responsiveness, we confer Ca(2+)-mediated activation of a CRE-containing promoter by introducing an expression vector for Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV). Activation could also be mediated directly by a constitutively active form of CaMKIV which is Ca2+ independent. The CaMKIV-mediated gene induction requires the activity of CREB/ATF family members but is independent of PKA activity. In contrast, transient expression of either a constitutively active or wild-type Ca2+/calmodulin-dependent protein kinase type II (CaMKII) fails to mediate the transactivation of the same CRE-containing reporter gene. Examination of the subcellular distribution of transiently expressed CaMKIV and CaMKII reveals that only CaMKIV enters the nucleus. Our results demonstrate that CaMKIV, which is expressed in neuronal, reproductive, and lymphoid tissues, may act as a mediator of Ca(2+)-dependent gene induction.

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Nuclear Translocation and DNA Recognition Signals Colocalized within the bZIP Domain of Cyclic Adenosine 3′,5′-Monophosphate Response Element-Binding Protein CREB

Cited by 62 publications

References 38 publications

Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival

Molecular Structure of the GARP Family of Plant Myb-Related DNA Binding Motifs of the Arabidopsis Response Regulators

Calcium/calmodulin-dependent protein kinase types II and IV differentially regulate CREB-dependent gene expression.

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