Deregulation of CRTCs in Aging and Age-Related Disease Risk

Escoubas, Caroline C.; Silva-García, Carlos Giovanni; Mair, William

doi:10.1016/j.tig.2017.03.002

Cited by 35 publications

(38 citation statements)

References 118 publications

(197 reference statements)

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“…CREB-regulated transcription coactivators (CRTCs) regulate multiple biological processes, including metabolism, cell transformation, memory and lifespan, and when disrupted cause age-related brain diseases 6 , 7 . The CRTC family comprises three members (CRTC1, CRTC2 and CRTC3) that are ubiquitously expressed, although CRTC1 is the main isoform expressed in neurons 8 .…”

Section: Introductionmentioning

confidence: 99%

CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters

Parra-Damas

Rubió-Ferrarons

Shen

et al. 2017

Sci Rep

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Gene expression mediated by the transcription factor cAMP-responsive element-binding protein (CREB) is essential for a wide range of brain processes. The transcriptional coactivartor CREB-regulated transcription coactivator-1 (CRTC1) is required for efficient induction of CREB target genes during neuronal activity. However, the mechanisms regulating induction of specific CREB/CRTC1-dependent genes during neuronal activity remain largely unclear. Here, we investigated the molecular mechanisms regulating activity-dependent gene transcription upon activation of the CREB/CRTC1 signaling pathway in neurons. Depolarization and cAMP signals induce preferential transcription of activity-dependent genes containing promoters with proximal CRE/TATA sequences, such as c-fos, Dusp1, Nr4a1, Nr4a2 and Ptgs2, but not genes with proximal CRE/TATA-less promoters (e.g. Nr4a3, Presenilin-1 and Presenilin-2). Notably, biochemical and chromatin immunoprecipitation analyses reveal constitutive binding of CREB to target gene promoters in the absence of neuronal activity, whereas recruitment of CRTC1 to proximal CRE/TATA promoters depends on neuronal activity. Neuronal activity induces rapid CRTC1 dephosphorylation, nuclear translocation and binding to endogenous CREB. These results indicate that neuronal activity induces a preferential binding of CRTC1 to the transcriptional complex in CRE/TATA-containing promoters to engage activity-dependent transcription in neurons.

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Section: Introductionmentioning

confidence: 99%

CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters

Parra-Damas

Rubió-Ferrarons

Shen

et al. 2017

Sci Rep

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“…, ; Escoubas et al . ). However, AAK‐2 has also been shown to regulate the activity of FoxO/DAF‐16 to modulate levels of neurodegeneration (Greer et al .…”

Section: Resultsmentioning

confidence: 97%

Non‐canonical activation of CREB mediates neuroprotection in a Caenorhabditis elegans model of excitotoxic necrosis

Feldmann

Chowdhury

Becker

et al. 2018

Journal of Neurochemistry

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Excitotoxicity, caused by exaggerated neuronal stimulation by Glutamate (Glu), is a major cause of neurodegeneration in brain ischemia. While we know that neurodegeneration is triggered by overstimulation of Glu‐receptors (GluRs), the subsequent mechanisms that lead to cellular demise remain controversial. Surprisingly, signaling downstream of GluRs can also activate neuroprotective pathways. The strongest evidence involves activation of the transcription factor cAMP response element‐binding protein (CREB), widely recognized for its importance in synaptic plasticity. Canonical views describe CREB as a phosphorylation‐triggered transcription factor, where transcriptional activation involves CREB phosphorylation and association with CREB‐binding protein. However, given CREB's ubiquitous cross‐tissue expression, the multitude of cascades leading to CREB phosphorylation, and its ability to regulate thousands of genes, it remains unclear how CREB exerts closely tailored, differential neuroprotective responses in excitotoxicity. A non‐canonical, alternative cascade for activation of CREB‐mediated transcription involves the CREB co‐factor cAMP‐regulated transcriptional co‐activator (CRTC), and may be independent of CREB phosphorylation. To identify cascades that activate CREB in excitotoxicity we used a Caenorhabditis elegans model of neurodegeneration by excitotoxic necrosis. We demonstrated that CREB's neuroprotective effect was conserved, and seemed most effective in neurons with moderate Glu exposure. We found that factors mediating canonical CREB activation were not involved. Instead, phosphorylation‐independent CREB activation in nematode excitotoxic necrosis hinged on CRTC. CREB‐mediated transcription that depends on CRTC, but not on CREB phosphorylation, might lead to expression of a specific subset of neuroprotective genes. Elucidating conserved mechanisms of excitotoxicity‐specific CREB activation can help us focus on core neuroprotective programs in excitotoxicity. Cover Image for this issue: doi: .

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“…CRTC1 bears an Arg-rich NLS 4, 34, but the molecular basis of its nuclear translocation remains unknown. To determine whether CRTC1 would be escorted into the nucleus by the classical NLS- dependent machinery, ivermectin was employed as a KPNA inhibitor, and importazol as a KPNB inhibitor 35, 36.…”

Section: Resultsmentioning

confidence: 99%

“…They interact with the basic Leu zipper (bZIP) domain of CREB and co-activate the transcriptional ability of CREB, recruiting TAF II 130 component of basal transcription factor TFIID followed by RNA polymerase II complex onto target promoters 1, 3. Deregulation of CRTCs has been implicated in age-related disease risk 4.…”

Section: Introductionmentioning

confidence: 99%

Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder

Yun¹,

Hong²,

Lee³

et al. 2019

Theranostics

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Rationale: SOX10 (SRY-related HMG-box 10) and MITF-M (microphthalmia-associated transcription factor M) restrict the expression of melanogenic genes, such as TYR (tyrosinase), in melanocytes. DACE (diacetylcaffeic acid cyclohexyl ester) inhibits melanin production in α-MSH (α-melanocyte stimulating hormone)-activated B16-F0 melanoma cells. In this study, we evaluated the antimelanogenic activity of DACE in vivo and elucidated the molecular basis of its action. Methods: We employed melanocyte cultures and hyperpigmented skin samples for pigmentation assays, and applied chromatin immunoprecipitation, immunoblotting, RT-PCR or siRNA-based knockdown for mechanistic analyses. Results: Topical treatment with DACE mitigated UV-B-induced hyperpigmentation in the skin with attenuated expression of MITF-M and TYR. DACE also inhibited melanin production in α-MSH- or ET-1 (endothelin 1)-activated melanocyte cultures. As a mechanism, DACE blocked the nuclear import of CRTC1 (CREB-regulated co-activator 1) in melanocytes. DACE resultantly inhibited SOX10 induction, and suppressed the transcriptional abilities of CREB/CRTC1 heterodimer and SOX10 at MITF-M promoter, thereby ameliorating facultative melanogenesis. Furthermore, this study unveiled new issues in melanocyte biology that i) KPNA1 (Impα5) escorted CRTC1 as a cargo across the nuclear envelope, ii) SOX10 was inducible in the melanogenic process, and iii) CRTC1 could direct SOX10 induction at the transcription level. Conclusion: We propose the targeting of CRTC1 as a unique strategy in the treatment of acquired pigmentary disorders.

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Deregulation of CRTCs in Aging and Age-Related Disease Risk

Cited by 35 publications

References 118 publications

CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters

CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters

Non‐canonical activation of CREB mediates neuroprotection in a Caenorhabditis elegans model of excitotoxic necrosis

Nuclear Entry of CRTC1 as Druggable Target of Acquired Pigmentary Disorder

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