Inducible cAMP Early Repressor Regulates the Period 1 Gene of the Hepatic and Adrenal Clocks

Zmrzljak, Uršula Prosenc; Korenčič, Anja; Košir, Rok; Goličnik, Marko; Sassone–Corsi, Paolo; Rozman, Damjana

doi:10.1074/jbc.m112.445692

Cited by 11 publications

(11 citation statements)

References 41 publications

(57 reference statements)

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“…The most common amplified region among both post-PHx and spontaneous tumors was the one on chromosome 18, containing 22 unique genes: it was amplified in 4/6 post PHx tumors and in 3/6 spontaneous tumors (Figure 3C , Supplemental Table 2 ). We focused on the gene Crem encoded by this region due to its involvement in cancer [ 12 , 13 ], including HCC metastasis [ 14 ], LR following PHx [ 15 ], and circadian regulation [ 16 ]. Using semi-qRT-PCR of the matched tumor and non-tumor samples, we confirmed that Crem was over-expressed (FC>=1.8) in all tumor samples where it was amplified (FC >= 1.4) ( Supplemental Table 6 , Supplemental Figure 11 ).…”

Section: Resultsmentioning

confidence: 99%

Specific genomic and transcriptomic aberrations in tumors induced by partial hepatectomy of a chronically inflamed murine liver

et al. 2014

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Resection of hepatocellular carcinoma (HCC) tumors by partial hepatectomy (PHx) is associated with promoting hepatocarcinogenesis. We have previously reported that PHx promotes hepatocarcinogenesis in the Mdr2-knockout (Mdr2-KO) mouse, a model for inflammation-mediated HCC. Now, to explore the molecular mechanisms underlying the tumor-promoting effect of PHx, we compared genomic and transcriptomic profiles of HCC tumors developing in the Mdr2-KO mice either spontaneously or following PHx. PHx accelerated HCC development in these mice by four months. PHx-induced tumors had major chromosomal aberrations: all were amplifications affecting multiple chromosomes. Most of these amplifications were located near the acrocentric centromeres of murine chromosomes. Four different chromosomal regions were amplified each in at least three tumors. The human orthologs of these common amplified regions are known to be amplified in HCC. All tumors of untreated mice had chromosomal aberrations, including both deletions and amplifications. Amplifications in spontaneous tumors affected fewer chromosomes and were not located preferentially at the chromosomal edges. Comparison of gene expression profiles revealed a significantly enriched expression of oncogenes, chromosomal instability markers and E2F1 targets in the post-PHx compared to spontaneous tumors. Both tumor groups shared the same frequent amplification at chromosome 18. Here, we revealed that one of the regulatory genes encoded by this amplified region, Crem, was over-expressed in the nuclei of murine and human HCC cells in vivo, and that it stimulated proliferation of human HCC cells in vitro. Our results demonstrate that PHx of a chronically inflamed liver directed tumor development to a discrete pathway characterized by amplification of specific chromosomal regions and expression of specific tumor-promoting genes. Crem is a new candidate HCC oncogene frequently amplified in this model and frequently over-expressed in human HCC.

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Section: Resultsmentioning

confidence: 99%

Specific genomic and transcriptomic aberrations in tumors induced by partial hepatectomy of a chronically inflamed murine liver

et al. 2014

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“…; Zmrzljak et al . ) and Per1 gene expression is maximally affected in mice deficient for the CREB‐related transcription factor cAMP‐responsive element modulator (CREM) (Zmrzljak et al . ).…”

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confidence: 99%

Period1 gates the circadian modulation of memory‐relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK

Rawashdeh

Jilg

Maronde

et al. 2016

Journal of Neurochemistry

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Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response elementbinding protein (CREB) are central to the circadian (~24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memoryrelevant hippocampal signaling pathways. We found that in wildtype mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1 À/À ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1 À/À mice, however, pP90RSK remained perinuclear. A coimmunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1.

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“…In agreement with our findings in goldfish liver, the AC/ PKA intracellular pathway has been linked to the molecular functioning of endogenous clocks in some phylogenetically distant species. cAMP, which activates PKA, is a stabilizer and modulator of per gene transcripts in the fruit fly Drosophila melanogaster and mammals (Hastings et al, 2014;Motzkus et al, 2000;Zmrzljak et al, 2013). Moreover, PKA induces Per1 expression in humans (Motzkus et al, 2007) and adjusts endogenous clocks in the presence of light pulses (Tischkau et al, 2000), and its inhibition delays the mammalian clock (Lee et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Ghrelin induces clock gene expression in the liver of goldfish in vitro via protein kinase C and protein kinase A pathways

Sánchez-Bretaño

Blanco

Alonso-Gómez

et al. 2017

Journal of Experimental Biology

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The liver is the most important link between the circadian system and metabolism. As a food-entrainable oscillator, the hepatic clock needs to be entrained by food-related signals. The objective of the present study was to investigate the possible role of ghrelin (an orexigenic peptide mainly synthesized in the gastrointestinal tract) as an endogenous synchronizer of the liver oscillator in teleosts. To achieve this aim, we first examined the presence of ghrelin receptors in the liver of goldfish. Then, the ghrelin regulation of clock gene expression in the goldfish liver was studied. Finally, the possible involvement of the phospholipase C/protein kinase C (PLC/ PKC) and adenylate cyclase/protein kinase A (AC/PKA) intracellular signalling pathways was investigated. Ghrelin receptor transcripts, ghs-r1a, are present in the majority of goldfish hepatic cells. Ghrelin induced the mRNA expression of the positive (gbmal1a, gclock1a) and negative (gper genes) elements of the main loop of the molecular clock machinery, as well as grev-erbα (auxiliary loop) in cultured liver. These effects were blocked, at least in part, by a ghrelin antagonist. Incubation of liver with a PLC inhibitor (U73122), a PKC activator ( phorbol 12-myristate 13-acetate) and a PKC inhibitor (chelerythrine chloride) demonstrated that the PLC/PKC pathway mediates such ghrelin actions. Experiments with an AC activator (forskolin) and a PKA inhibitor (H89) showed that grev-erbα regulation could be due to activation of PKA. Taken together, the present results show for the first time in vertebrates a direct action of ghrelin on hepatic clock genes and support a role for this hormone as a temporal messenger in the entrainment of liver circadian functions.

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Inducible cAMP Early Repressor Regulates the Period 1 Gene of the Hepatic and Adrenal Clocks

Cited by 11 publications

References 41 publications

Specific genomic and transcriptomic aberrations in tumors induced by partial hepatectomy of a chronically inflamed murine liver

Specific genomic and transcriptomic aberrations in tumors induced by partial hepatectomy of a chronically inflamed murine liver

Period1 gates the circadian modulation of memory‐relevant signaling in mouse hippocampus by regulating the nuclear shuttling of the CREB kinase pP90RSK

Ghrelin induces clock gene expression in the liver of goldfish in vitro via protein kinase C and protein kinase A pathways

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