Deregulation of CRTCs in Aging and Age-Related Disease Risk

doi:10.1016/j.tig.2017.03.002

Trends in Genetics

Volume 33, Issue 5, May 2017, Pages 303-321

https://doi.org/10.1016/j.tig.2017.03.002 Get rights and content

Trends

Novel cellular regulators and targets of the CRTC family have recently been identified.

In C. elegans CRTCs have been shown to modulate aging.

Recently CRTC dysfunction has been associated with age-related human diseases.

CRTCs could provide a target for healthy human aging.

Advances in public health in the past century have seen a sharp increase in human life expectancy. With these changes have come an increased prevalence of age-related pathologies and health burdens in the elderly. Patient age is the biggest risk factor for multiple chronic conditions that often occur simultaneously within a single individual. An alternative to disease-centric therapeutic approaches is that of ‘geroscience’, which aims to define molecular mechanisms that link age to overall disease risk. One such mechanism is deregulation of CREB-regulated transcriptional coactivators (CRTCs). Initially identified for their role in modulating CREB transcription, the past 5 years has seen an expansion in knowledge of new cellular regulators and roles of CRTCs beyond CREB. CRTCs have been shown to modulate organismal aging in Caenorhabditis elegans and to impact on age-related diseases in humans. We discuss CRTC deregulation as a new driver of aging that integrates the link between age and disease risk.

Section snippets

Aging as a Treatable Risk Factor

Public Health and Medical advances in the past century have yielded significant increases in human life expectancy. In 1955, worldwide average life expectancy was 46, but by 2015 this number had risen by nearly 20 years to 65 [1]. Because developing countries continue to get access to better healthcare, this trend is set to continue such that, by 2100, at least half of the human population worldwide can expect to live to 83 years of age [1] (Figure 1). The resulting shift in our population

Outputs Beyond CREB: Emerging Roles for CRTCs

Initially named transducers of regulated CREB (TORCs) or mucoepidermoid carcinoma translocated protein (MECTs), CRTC family members were first identified as coactivators of the transcription factor CREB in view of their ability to induce CREB target gene expression in the absence of a cAMP stimulus 7, 8, 9, 10. However, recent work has identified expanding roles for CRTCs outside the confines of their name, showing that CRTCs act both as regulators of transcription factors beyond CREB and of

Inputs: Post-translational Regulators of CRTCs and Aging

CRTCs are extensively post-translationally regulated, and many CRTC regulators have known roles in the modulation of aging (Table 1). CRTCs are negatively regulated through phosphorylation by AMP-activated protein kinase (AMPK) family kinases, including salt-inducible kinases 1, 2, and 3 (SIK1/2/3) 14, 24, 25, AMPK 10, 14, and microtubule affinity regulating kinase 2 (MARK2) [26]. Phosphorylation by these kinases facilitates 14-3-3 protein binding and retention of CRTCs in the cytoplasm (Figure

CRTCs and Metabolic Disorders

Homeostatic regulation of metabolism is crucial for maintaining health throughout life. Metabolic disorders such as obesity not only impact on quality of life but also reduce life expectancy and expedite the onset of multiple age-related diseases beyond type II diabetes, including cancer and neurodegeneration [35]. As such, obesity can be viewed as an accelerated-aging phenotype, adding the pandemic of obesity as a contributor to the increase in age-onset diseases [36]. CRTC family proteins are

CRTCs and Cancer Cell Proliferation

Another crucial disease for which age is a potent risk factor is cancer (Figure 4), and CRTCs have been implicated in carcinogenesis in several conditions, including lung cancer, colorectal cancer, acute myeloid leukemia, mucoepidermoid carcinoma, and esophageal adenocarcinoma 4, 5, 66, 67, 68, 69, 70, 71, 72, 73, 74. Mechanistic links between CRTCs and cancer are only beginning to emerge but often involve hypophosphorylation of CRTC1 and upregulation of target gene expression. Liver kinase B1

CRTCs Function in Learning, Memory, and Neurodegenerative Diseases

CREB has an evolutionarily conserved fundamental role in regulating memory formation and memory consolidation 81, 82, 83. The cAMP–CREB pathway controls memory for example by enhancing synaptic transmission or increasing neuronal excitability [81]. Modulating CREB levels or its binding partner the histone acetyltransferase CBP (CREB binding protein) by overexpression or knockout results in either enhanced memory formation or memory deficits, respectively, in mammalian models [81]. Even though

Concluding Remarks

As recent work has conclusively shown, CREB-regulated transcriptional coactivators play broader cellular roles than was initially thought (Boxes 2 and 3). Being neither regulated by CREB nor exclusively transcriptional coactivators, perhaps the time has come for a rethink of their – with hindsight – somewhat myopic name. Although ‘cAMP-regulated transcriptional coactivator’ has been suggested, until more work is done on these understudied proteins a name that adequately encompasses their

Acknowledgments

We apologize to those not cited due to space limitations. We thank members of the Mair Lab for useful discussion. W.B.M. is funded by the NIH R01AG044346 and NIH R01AG054201. C.C.E. is funded the Ligue Nationale contre le Cancer. C.G.S-G. is funded by the Yerby Postdoctoral Fellowship. We thank the Library of Science and Medical Illustrations for providing the images used to create the figures in this review.

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Cited by (30)

CRTC1 signaling involvement in depression-like behavior of prenatally stressed offspring rat
2021, Behavioural Brain Research
Citation Excerpt :
This was in accordance with the discovery of Martinowich et al. [9], which indicated that the expression of BDNF in the HIP and prefrontal cortex (PFC) decreased in patients with depression and anxiety. More recently, CREB-regulated transcriptional coactivators (CRTCs, also known as TORCs) have been shown to be involved in the pathogenesis of depression, which emerged as novel transcriptional regulators of essential biological functions, including brain plasticity [10,11]. CRTC1, one isoform of the CRTC family, is the most abundantly expressed isoform in the brain, particularly in hippocampal neurons [12].
A large body of literature has demonstrated that prenatal stress (PS) can induce depression-like behavior in the offspring. However, the underlying mechanism remains largely unknown. CREB-regulated transcriptional coactivator 1(CRTC1) has recently been shown to involve in mood regulation. This research aims to investigate whether CRTC1 signaling was involved in the depression-like behavior of prenatally stressed offspring rats. Sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT) were adopted to test the depression-like behavior in the male offspring rats, and CRTC1 signaling was measured. The results showed that there were significantly reduced sucrose intake in SPT and prolonged immobility time in FST in PS-exposure offspring rats. It was also found decreased levels of total CRTC1, nuclear CRTC1, calcineurin, brain-derived neurotrophic factor (BDNF) and c-fos, but increased cytoplasmic p-CRTC1 in the hippocampus (HIP) and prefrontal cortex (PFC) of the offspring rats. Furthermore, the mRNA level of CRTC1, calcineurin, BDNF, c-fos were down-regulated. Abnormal expression of CRTC1 signaling could be alleviated by fluoxetine treatment. In conclusion, our research indicated that the aberration of CRTC1 expression and/or phosphorylation activity might play a vital role in PS-induced depression-like behavior of offspring rats.
Imipramine exerts antidepressant-like effects in chronic stress models of depression by promoting CRTC1 expression in the mPFC
2020, Brain Research Bulletin
Recent studies have suggested that CREB-regulated transcription coactivator 1 (CRTC1) plays a role in the pathophysiology of depression. Although imipramine is thought to prevent the reuptake of synaptic serotonin and norepinephrine, its antidepressant-like mechanisms remain elusive. In this study, the effects of imipramine on CRTC1 were studied in several models of depression, including the chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS) models. We examined whether repeated imipramine administration can reverse the effects of CRS, CUMS and CSDS on CRTC1 expression in both the hippocampus and medial prefrontal cortex (mPFC). Furthermore, genetic knockdown of CRTC1 by CRTC1-shRNA was used to determine whether CRTC1 is necessary for the antidepressant-like effects of imipramine in mice. Our results showed that imipramine reversed the down-regulating effects of CRS, CUMS and CSDS on CRTC1 expression in the mPFC but not the hippocampus, and that CRTC1-shRNA fully abolished the antidepressant-like actions of imipramine in mice. In conclusion, CRTC1 in the mPFC is involved in the antidepressant mechanism of imipramine.
(Epi)genetic regulation of CRTC1 in human eating behaviour and fat distribution
2019, EBioMedicine
Citation Excerpt :
While CRTC2 plays a role in liver gluconeogenesis during fasting [7], CRTC3 contributes to adipocyte biology and fat distribution [8]. Most studies however focused on CRTC1 which is highest expressed in the brain, specifically in prefrontal cortex, amygdala, hippocampus, and hypothalamus, hence has a central role in regulating diverse pathways [3,9,10]. CRTC1 is involved in learning and memory formation [11,12], in pathways controlling mood [3,4], regulates longevity [10], locomotor activity [13], and also energy metabolism [3,14,15], eating behaviour and obesity and diabetes development [6,2,3,14,16,17].
In brain, CREB-regulated transcription co-activator 1 (CRTC1) is involved in metabolic dysregulation. In humans a SNP in CRTC1 was associated to body fat percentage and two SNPs affected RNA Pol II binding and chromatin structure, implying epigenetic regulation of CRTC1. We sought to understand the relevance of CRTC1 SNPs, DNA methylation and expression in human eating behaviour and its relationship to clinical variables of obesity in blood and adipose tissue.
13 CRTC1 SNPs were included to analyze eating behaviour. For rs7256986, follow up association analyses were applied on DNA methylation, CRTC1 expression and clinical parameters. Linear regression was used throughout the study adjusted for age, sex and BMI. Besides data extraction from previous work, rs7256986 was de-novo genotyped and DNA methylation was evaluated by using pyrosequencing.
We found several SNPs in the CRTC1 locus nominally associated with human eating behaviour or 2hr postprandial insulin levels and observed a correlation with alcohol and coffee intake (all P < 0.05). G-allele carriers of rs7256986 showed slightly increased hip circumference. We showed that rs7256986 represents a methylation quantitative trait locus (meQTL) in whole blood and adipose tissue. The presence of the SNP and/or DNA methylation correlated with CRTC1 gene expression which in turn, related to BMI and fat distribution.
Our data support the known role of CRCT1 regulating energy metabolism in brain. Here, we highlight relevance of CRTC1 regulation in blood and adipose tissue.
IFB AdiposityDiseases (BMBF); n609020-Scientia Fellows; Helse-SørØst; DFG: CRC 1052/1 and/2; Kompetenznetz Adipositas, German Diabetes Association.
Hippocampal Salt-Inducible Kinase 2 Plays a Role in Depression via the CREB-Regulated Transcription Coactivator 1–cAMP Response Element Binding–Brain-Derived Neurotrophic Factor Pathway
2019, Biological Psychiatry
Developing novel pharmacological targets beyond monoaminergic systems is now a popular strategy for finding new ways to treat depression. Salt-inducible kinase (SIK) is a kinase that regulates the nuclear translocation of cyclic adenosine monophosphate response element binding protein (CREB)-regulated transcription coactivator (CRTC) by phosphorylation. Here, we hypothesize that dysfunction of the central SIK-CRTC system may contribute to the pathogenesis of depression.
Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression, various behavioral tests, viral-mediated gene transfer, Western blotting, coimmunoprecipitation, quantitative real-time reverse transcription polymerase chain reaction, and immunohistochemistry were used in this study (for in vivo studies, n = 10; for in vitro studies, n = 5).
Both CSDS and CUMS markedly increased the expression of hippocampal SIK2, which reduced CRTC1 nuclear translocation and binding of CRTC1 and CREB in the hippocampus. Genetic overexpression of hippocampal SIK2 in naïve mice simulated chronic stress, inducing depressive-like behaviors in the forced swim test, tail suspension test, sucrose preference test, and social interaction test, as well as decreasing the brain-derived neurotrophic factor signaling cascade and neurogenesis in the hippocampus. In contrast, genetic knockdown and knockout of hippocampal SIK2 protected against CSDS and CUMS, exerting significant antidepressant-like effects that were mediated via the downstream CRTC1-CREB–brain-derived neurotrophic factor pathway. Moreover, fluoxetine, venlafaxine, and mirtazapine all significantly restored the effects of CSDS and CUMS on the hippocampal SIK2-CRTC1 pathway, which was necessary for their antidepressant actions.
The hippocampal SIK2-CRTC1 pathway is involved in the pathogenesis of depression, and hippocampal SIK2 could be a novel target for the development of antidepressants.
Adaptive Transcriptional Responses by CRTC Coactivators in Cancer
2019, Trends in Cancer
Citation Excerpt :
CRTCs are a newly discovered, conserved family of cell signaling integrators [18,21]. There are three CRTCs (CRTC1–3) in humans sharing common domains [22], while Caenorhabditis elegans and Drosophila melanogaster have only one functional CRTC homolog each, termed CRTC-1 and crtc respectively [22,23]. Structurally, CRTCs contain a conserved N-terminal coiled coil that forms the CREB-binding domain (CBD), a central regulatory domain (RD), a serine/glutamine-rich splicing domain (SD), and a C-terminal transactivation domain (TAD) [22,24] (Figure 1, left).
Adaptive stress signaling networks directly influence tumor development and progression. These pathways mediate responses that allow cancer cells to cope with both tumor cell-intrinsic and cell-extrinsic insults and develop acquired resistance to therapeutic interventions. This is mediated in part by constant oncogenic rewiring at the transcriptional level by integration of extracellular cues that promote cell survival and malignant transformation. The cAMP-regulated transcriptional coactivators (CRTCs) are a newly discovered family of intracellular signaling integrators that serve as the conduit to the basic transcriptional machinery to regulate a host of adaptive response genes. Thus, somatic alterations that lead to CRTC activation are emerging as key driver events in the development and progression of many tumor subtypes.
Mechanistic role of the CREB-regulated transcription coactivator 1 in cardiac hypertrophy
2019, Journal of Molecular and Cellular Cardiology
The sympathetic nervous system is the main stimulator of cardiac function. While acute activation of the β-adrenoceptors exerts positive inotropic and lusitropic effects by increasing cAMP and Ca²⁺, chronically enhanced sympathetic tone with changed β-adrenergic signaling leads to alterations of gene expression and remodeling. The CREB-regulated transcription coactivator 1 (CRTC1) is activated by cAMP and Ca²⁺. In the present study, the regulation of CRTC1 in cardiomyocytes and its effect on cardiac function and growth was investigated. In cardiomyocytes, isoprenaline induced dephosphorylation, and thus activation of CRTC1, which was prevented by propranolol. Crtc1-deficient mice exhibited left ventricular dysfunction, hypertrophy and enlarged cardiomyocytes. However, isoprenaline-induced contractility of isolated trabeculae or phosphorylation of cardiac troponin I, cardiac myosin-binding protein C, phospholamban, and ryanodine receptor were not altered, suggesting that cardiac dysfunction was due to the global lack of Crtc1. The mRNA and protein levels of the Gα_q GTPase activating protein regulator of G-protein signaling 2 (RGS2) were lower in hearts of Crtc1-deficient mice. Chromatin immunoprecipitation and reporter gene assays showed stimulation of the Rgs2 promoter by CRTC1. In Crtc1-deficient cardiomyocytes, phosphorylation of the Gα_q-downstream kinase ERK was enhanced. CRTC1 content was higher in cardiac tissue from patients with aortic stenosis or hypertrophic cardiomyopathy and from two murine models mimicking these diseases. These data suggest that increased CRTC1 in maladaptive hypertrophy presents a compensatory mechanism to delay disease progression in part by enhancing Rgs2 gene transcription. Furthermore, the present study demonstrates an important role of CRTC1 in the regulation of cardiac function and growth.

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^‡: These authors contributed equally to this work.

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Trends in Genetics

Feature ReviewDeregulation of CRTCs in Aging and Age-Related Disease Risk

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Section snippets

Aging as a Treatable Risk Factor

Outputs Beyond CREB: Emerging Roles for CRTCs

Inputs: Post-translational Regulators of CRTCs and Aging

CRTCs and Metabolic Disorders

CRTCs and Cancer Cell Proliferation

CRTCs Function in Learning, Memory, and Neurodegenerative Diseases

Concluding Remarks

Acknowledgments

Cell

Cell

Mol. Cell

Curr. Biol.

Cell

Cell

Cell Metab.

Trends Genet.

Cell

Trends Immunol.

Cell Metab.

J. Biol. Chem.

Cell Rep.

Cell Metab.

J. Biol. Chem.

Cell

Mol. Cancer

Cell Rep.

Trends Neurosci.

Mol. Brain

Neuron

Biol. Psychiatry

Neuropharmacology

Cell

Neuron

Cell Rep.

Aging and survival: the genetics of life span extension by dietary restriction

Annu. Rev. Biochem.

Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB

Nature

CREB and the CRTC co-activators: sensors for hormonal and metabolic signals

Nat. Rev. Mol. Cell Biol.

Identification of a family of cAMP response element-binding protein coactivators by genome-scale functional analysis in mammalian cells

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

The Creb1 coactivator Crtc1 is required for energy balance and fertility

Nat. Med.

TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity

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

Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogenesis in muscle cells

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

The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism

Nature

CRTC3 links catecholamine signalling to energy balance

Nature

Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2

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

The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis

Nature

The coactivator CRTC1 promotes cell proliferation and transformation via AP-1

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

Transcriptional regulation of autophagy by an FXR–CREB axis

Nature

ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis

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

Bipartite functions of the CREB co-activators selectively direct alternative splicing or transcriptional activation

EMBO J.

The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1

Nature

Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans

Nature

Silencing the constitutive active transcription factor CREB by the LKB1–SIK signaling cascade

FEBS J.

Phosphorylation of the CREB-specific coactivator TORC2 at Ser307 regulates its intracellular localization in COS-7 cells and in the mouse liver

American Journal of Physiology - Endocrinology and Metabolism

Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2

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

Suppressor of MEK null (SMEK)/protein phosphatase 4 catalytic subunit (PP4C) is a key regulator of hepatic gluconeogenesis

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

Feature Review
Deregulation of CRTCs in Aging and Age-Related Disease Risk