Re-thinking cell cycle regulators: the cross-talk with metabolism

Fajas, Lluís

doi:10.3389/fonc.2013.00004

Cited by 73 publications

(66 citation statements)

References 58 publications

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“…In recent years, a growing body of evidence supports the emerging notion that cell cycle regulatory proteins contribute to metabolic processes in addition to, or linked with, their role in cell growth (17,28). Today, these proteins are perceived as sensors of external signals that …”

Section: Discussionmentioning

confidence: 99%

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Cdkn2a/p16Ink4a Regulates Fasting-Induced Hepatic Gluconeogenesis Through the PKA-CREB-PGC1α Pathway

et al. 2014

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Type 2 diabetes (T2D) is hallmarked by insulin resistance, impaired insulin secretion, and increased hepatic glucose production. The worldwide increasing prevalence of T2D calls for efforts to understand its pathogenesis in order to improve disease prevention and management. Recent genome-wide association studies have revealed strong associations between the CDKN2A/B locus and T2D risk. The CDKN2A/B locus contains genes encoding cell cycle inhibitors, including p16 Ink4a, which have not yet been implicated in the control of hepatic glucose homeostasis. Here, we show that p16Ink4a deficiency enhances fasting-induced hepatic glucose production in vivo by increasing the expression of key gluconeogenic genes. p16Ink4a downregulation leads to an activation of PKA-CREB-PGC1a signaling through increased phosphorylation of PKA regulatory subunits. Taken together, these results provide evidence that p16Ink4a controls fasting glucose homeostasis and could as such be involved in T2D development.Type 2 diabetes (T2D) is a complex metabolic disorder involving a combination of insulin resistance, impaired insulin secretion, and increased hepatic glucose production (1,2). The pathogenesis of T2D is multifactorial, involving both genetic and environmental susceptibility factors (3). During these last few years, the search for genetic determinants of T2D greatly progressed, identifying new loci contributing to T2D. A better understanding of the function of the gene products of these loci is required to identify new strategies for the prevention and treatment of T2D (3,4). Hence, recent human genomewide association studies (GWAS) have identified a polymorphism on chromosome 9p21 (rs10811661), located 125 kb upstream of the CDKN2B and CDKN2A genes, that is strongly and reproducibly linked to T2D (5-7), establishing genes on the CDKN2A/B locus among the strongest candidates for conferring susceptibility to T2D across different ethnicities (4).The gene products are the cyclin-dependent kinase (CDK) inhibitors p16Ink4a and p14 ARF for the CDKN2A locus and p15Ink4b for the CDKN2B locus, which are tumor suppressors acting as cell cycle inhibitors (8,9). The p15Ink4b and p16 Ink4a proteins bind to either CDK4 or CDK6, thus inhibiting the action of cyclin D and preventing retinoblastoma protein phosphorylation and subsequent release of the E2F1 transcription factor. As a consequence, the transcription of genes required for cell cycle progression to the S phase is restrained.However, how the CDKN2A/B gene products modulate glucose metabolism is less clear. In murine models, increased expression of p15Ink4b in pancreatic islets is associated with islet hypoplasia and impaired glucose-induced insulin secretion (10). Moreover, p16Ink4a plays a crucial role in senescence and aging. p16Ink4a expression increases with age in pancreatic b-cells and promotes an agedependent decline in islet regenerative potential (11). Additionally, other cell cycle regulators, like CDK4, E2F1, and cyclin D, also play roles in glucose homeostasis through

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Section: Discussionmentioning

confidence: 99%

“…) in metabolic control has been described in tissues such as adipose tissue and the pancreas (28), this is the first study that demonstrates a role of a cell cycle regulator, p16…”

Section: Ink4cmentioning

confidence: 99%

Cdkn2a/p16Ink4a Regulates Fasting-Induced Hepatic Gluconeogenesis Through the PKA-CREB-PGC1α Pathway

et al. 2014

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“…De manière surprenante, les souris Cdk4 R24C/R24C , qui ont une prise de poids plus importante, présentent une amélio-ration de la sensibilité à l'insuline et de la tolérance au glucose, à l'inverse des souris invalidées pour CDK4 dans le tissu adipeux (Cdk4 flox/flox ) qui présentent une sensibilité à l'insuline diminuée. Nous avons également pu mettre en évidence par des expériences de biologie moléculaire que CDK4 est une protéine [4,5]. Depuis leur découverte, les virus géants ont révélé des caractéristiques phénotypiques et génotypiques uniques qui vont à l'encontre de la définition classique d'un virus, les plaçant à proximité de certains microbes.…”

Section: Activité De Cdk4 Dans Le Tissu Adipeux De Patients Obèsesunclassified

“…Ces modifications du métabolisme énergétique des cellules cancéreuses commencent à être bien documentées [4]. Partant de ce postulat, nous nous sommes interrogés sur le rôle que jouent les facteurs du cycle cellulaire dans le contrôle du métabolisme énergé-tique, et notamment les protéines de la voie CDK4-Rb-E2F1 (cyclin-dependent kinase 4 -protéine du rétinoblastome -E2F transcription factor 1) [5]. Le facteur de transcription E2F1 et ses régulateurs, la protéine du rétinoblas-tome Rb1 et la kinase dépendante des cyclines CDK4, sont bien décrits dans la littérature pour leur rôle dans la progression du cycle cellulaire [6,7].…”

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Contrôle de l’homéostasie glucido-lipidique par les facteurs du cycle cellulaire CDK4 et E2F1

Denechaud¹,

López-Mejía²,

Fajas³

2016

Med Sci (Paris)

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“…In the absence of Rb, proapoptotic proteins can accumulate, making cells more sensitive to stress-induced apoptosis. Rb also controls metabolic reactions that impinge upon the ability of mitochondria to generate ATP under conditions of stress (15,16). Rb loss can decrease cell energy expenditure (17), and direct glutamine catabolism toward the production of glutathione and therefore away from anaplerotic supplementation of the TCA pathway (10,18).…”

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confidence: 99%

Deficiencies in Cellular Processes Modulated by the Retinoblastoma Protein Do Not Account for Reduced Human Cytomegalovirus Replication in Its Absence

VanDeusen

Kalejta

2015

J Virol

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Despite encoding multiple viral proteins that modulate the retinoblastoma (Rb) protein in a manner classically defined as inactivation, human cytomegalovirus (HCMV) requires the presence of the Rb protein to replicate efficiently. In uninfected cells, Rb controls numerous pathways that the virus also commandeers during infection. These include cell cycle progression, senescence, mitochondrial biogenesis, apoptosis, and glutaminolysis. We investigated whether a potential inability of HCMV to regulate these Rb-controlled pathways in the absence of the Rb protein was the reason for reduced viral productive replication in Rb knockdown cells. We found that HCMV was equally able to modulate these pathways in the parental Rb-expressing and Rb-depleted cells. Our results suggest that Rb may be required to enhance a specific viral process during HCMV productive replication. R etinoblastoma (Rb) protein function is modified by multiple viruses (1-3). Through transcriptional repression of the E2F-responsive genes required for DNA replication, hypophosphorylated (active) Rb impedes cell cycle transit through G 1 and into S phase (4). Rb can also induce the formation of heterochromatin at E2F responsive genes, leading to permanent transcriptional silencing and replicative senescence (5, 6), providing a tumor suppressive function. As the role of Rb as a mediator of senescence and restrictor of cell cycle progression has long been acknowledged, the prevailing model in the field of DNA virology has associated viral targeting of Rb with maintaining a cell cycle state conducive to viral replication (7). Specifically, it was proposed that viruses alter the function of Rb to provide an S-phase-like environment where the enzymes and small molecule precursors necessary for DNA synthesis would be readily available for viral DNA replication. Indeed, the ability of the E7 protein of the high-risk human papillomavirus strain 16 to bind Rb is necessary for viral DNA replication (8).However, we recently reported that transient and stable Rb knockdown reduces the efficiency of human cytomegalovirus (HCMV) DNA synthesis and productive replication (9). This result was unexpected as HCMV encodes at least four viral proteins reported to modify several biological functions of Rb (2). Therefore, the relationship between viruses and Rb appears more complicated than the current paradigm allows.In recent years Rb has been shown to affect many facets of mitochondrial function in addition to its critical role in controlling the cell cycle. These include mitochondrial biogenesis, apoptosis, and the utilization of glutamine for the tricarboxylic acid (TCA) cycle and the production of glutathione. In the absence of Rb, cells have lower ratios of mitochondrial to cellular DNA, and this has been ascribed to defects in mitochondrial biogenesis (10,11). Rb regulates apoptosis directly at the mitochondria by binding to Bax (12,13). Interestingly, it is a phosphorylated form of Rb that interacts with Bax, and loss of this form can trigger apoptosis (12...

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Re-thinking cell cycle regulators: the cross-talk with metabolism

Cited by 73 publications

References 58 publications

Cdkn2a/p16Ink4a Regulates Fasting-Induced Hepatic Gluconeogenesis Through the PKA-CREB-PGC1α Pathway

Cdkn2a/p16Ink4a Regulates Fasting-Induced Hepatic Gluconeogenesis Through the PKA-CREB-PGC1α Pathway

Contrôle de l’homéostasie glucido-lipidique par les facteurs du cycle cellulaire CDK4 et E2F1

Deficiencies in Cellular Processes Modulated by the Retinoblastoma Protein Do Not Account for Reduced Human Cytomegalovirus Replication in Its Absence

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