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Genes, Volume 4, Issue 1 (March 2013) – 5 articles , Pages 1-100

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323 KiB

Open AccessArticle

Adenosine Triphosphate (ATP) Is a Candidate Signaling Molecule in the Mitochondria-to-Nucleus Retrograde Response Pathway

by Feng Zhang, Tammy Pracheil, Janet Thornton and Zhengchang Liu

Genes 2013, 4(1), 86-100; https://doi.org/10.3390/genes4010086 - 20 Mar 2013

Cited by 43 | Viewed by 10347

Abstract

Intracellular communication from the mitochondria to the nucleus is achieved via the retrograde response. In budding yeast, the retrograde response, also known as the RTG pathway, is regulated positively by Rtg1, Rtg2, Rtg3 and Grr1 and negatively by Mks1, Lst8 and two 14-3-3 proteins, Bmh1/2. Activation of retrograde signaling leads to activation of Rtg1/3, two basic helix-loop-helix leucine zipper transcription factors. Rtg1/3 activation requires Rtg2, a cytoplasmic protein with an N-terminal adenosine triphosphate (ATP) binding domain belonging to the actin/Hsp70/sugar kinase superfamily. The critical regulatory step of the retrograde response is the interaction between Rtg2 and Mks1. Rtg2 binds to and inactivates Mks1, allowing for activation of Rtg1/3 and the RTG pathway. When the pathway is inactive, Mks1 has dissociated from Rtg2 and bound to Bmh1/2, preventing activation of Rtg1/3. What signals association or disassociation of Mks1 and Rtg2 is unknown. Here, we show that ATP at physiological concentrations dissociates Mks1 from Rtg2 in a highly cooperative fashion. We report that ATP-mediated dissociation of Mks1 from Rtg2 is conserved in two other fungal species, K. lactis and K. waltii. Activation of Rtg1/3 upregulates expression of genes encoding enzymes catalyzing the first three reactions of the Krebs cycle, which is coupled to ATP synthesis through oxidative phosphorylation. Therefore, we propose that the retrograde response is an ATP homeostasis pathway coupling ATP production with ATP-mediated repression of the retrograde response by releasing Mks1 from Rtg2. Full article

(This article belongs to the Special Issue Signal Transduction)

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198 KiB

Open AccessArticle

Gene Expressions for Signal Transduction under Acidic Conditions

by Toshihiko Fukamachi, Syunsuke Ikeda, Xin Wang, Hiromi Saito, Masatoshi Tagawa and Hiroshi Kobayashi

Genes 2013, 4(1), 65-85; https://doi.org/10.3390/genes4010065 - 8 Mar 2013

Cited by 10 | Viewed by 6783

Abstract

Although it is now well known that some diseased areas, such as cancer nests, inflammation loci, and infarction areas, are acidified, little is known about cellular signal transduction, gene expression, and cellular functions under acidic conditions. Our group showed that different signal proteins were activated under acidic conditions compared with those observed in a typical medium of around pH 7.4 that has been used until now. Investigations of gene expression under acidic conditions may be crucial to our understanding of signal transduction in acidic diseased areas. In this study, we investigated gene expression in mesothelioma cells cultured at an acidic pH using a DNA microarray technique. After 24 h culture at pH 6.7, expressions of 379 genes were increased more than twofold compared with those in cells cultured at pH 7.5. Genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors numbered 35, 32, and 17 among the 379 genes, respectively. Since the functions of 78 genes are unknown, it can be argued that cells may have other genes for signaling under acidic conditions. The expressions of 37 of the 379 genes were observed to increase after as little as 2 h. After 24 h culture at pH 6.7, expressions of 412 genes were repressed more than twofold compared with those in cells cultured at pH 7.5, and the 412 genes contained 35, 76, and 7 genes encoding receptors, signal proteins including transcription factors, and cytokines including growth factors, respectively. These results suggest that the signal pathways in acidic diseased areas are different, at least in part, from those examined with cells cultured at a pH of around 7.4. Full article

(This article belongs to the Special Issue Signal Transduction)

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347 KiB

Open AccessArticle

Differential Effects of MicroRNAs on Glioblastoma Growth and Migration

by Duane Jeansonne, Marco Pacifici, Adam Lassak, Krzysztof Reiss, Giuseppe Russo, Jovanny Zabaleta and Francesca Peruzzi

Genes 2013, 4(1), 46-64; https://doi.org/10.3390/genes4010046 - 4 Mar 2013

Cited by 19 | Viewed by 7392

Abstract

Glioblastoma multiforme is characterized by rapid proliferation, aggressive metastatic potential, and resistance to radio- and chemotherapy. The matricellular protein CYR61 regulates cellular proliferation and migration and is highly expressed in Glioblastomas. MicroRNAs are 22-nucleotides long RNAs that regulate gene expression post-transcriptionally. Here, we utilized the LN229 glioblastoma cell line and found that CYR61 is a target of miR-136, miR-155, and miR-634. Over-expression of miR-136 and miR-634 miRNAs negatively affected proliferation, but not migration, while expression of miR-155 reduced migration but did not affect the proliferation of LN229 cells. Investigation of the molecular mechanisms affected by expression of miR-634 revealed an increased phosphorylation of p70S6 kinase, suggesting an induction of the mammalian target of rapamycin (mTOR) complex 1 pathway. Additionally, in miR-634 overexpressing cells, TSC2, a negative regulator of mTOR signaling, was found to be decreased. Altogether, our study provides insights on the differential roles of miRs-136, -155, and -634 in regulating glioblastoma cell growth and migration, and how microRNAs could be manipulated to decrease the aggressiveness and metastatic potential of tumor cells. Full article

(This article belongs to the Special Issue Signal Transduction)

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598 KiB

Open AccessReview

Matricellular Signal Transduction Involving Calmodulin in the Social Amoebozoan Dictyostelium

by Danton H. O'Day and Robert J. Huber

Genes 2013, 4(1), 33-45; https://doi.org/10.3390/genes4010033 - 15 Feb 2013

Viewed by 6370

Abstract

The social amoebozoan Dictyostelium discoideum undergoes a developmental sequence wherein an extracellular matrix (ECM) sheath surrounds a group of differentiating cells. This sheath is comprised of proteins and carbohydrates, like the ECM of mammalian tissues. One of the characterized ECM proteins is the cysteine-rich, EGF-like (EGFL) repeat-containing, calmodulin (CaM)-binding protein (CaMBP) CyrA. The first EGFL repeat of CyrA increases the rate of random cell motility and cyclic AMP-mediated chemotaxis. Processing of full-length CyrA (~63 kDa) releases two major EGFL repeat-containing fragments (~45 kDa and ~40 kDa) in an event that is developmentally regulated. Evidence for an EGFL repeat receptor also exists and downstream intracellular signaling pathways involving CaM, Ras, protein kinase A and vinculin B phosphorylation have been characterized. In total, these results identify CyrA as a true matricellular protein comparable in function to tenascin C and other matricellular proteins from mammalian cells. Insight into the regulation and processing of CyrA has also been revealed. CyrA is the first identified extracellular CaMBP in this eukaryotic microbe. In keeping with this, extracellular CaM (extCaM) has been shown to be present in the ECM sheath where it binds to CyrA and inhibits its cleavage to release the 45 kDa and 40 kDa EGFL repeat-containing fragments. The presence of extCaM and its role in regulating a matricellular protein during morphogenesis extends our understanding of CaM-mediated signal transduction in eukaryotes. Full article

(This article belongs to the Special Issue Signal Transduction)

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681 KiB

Open AccessReview

The Replication Fork: Understanding the Eukaryotic Replication Machinery and the Challenges to Genome Duplication

by Adam R. Leman and Eishi Noguchi

Genes 2013, 4(1), 1-32; https://doi.org/10.3390/genes4010001 - 29 Jan 2013

Cited by 73 | Viewed by 49154

Abstract

Eukaryotic cells must accurately and efficiently duplicate their genomes during each round of the cell cycle. Multiple linear chromosomes, an abundance of regulatory elements, and chromosome packaging are all challenges that the eukaryotic DNA replication machinery must successfully overcome. The replication machinery, the “replisome” complex, is composed of many specialized proteins with functions in supporting replication by DNA polymerases. Efficient replisome progression relies on tight coordination between the various factors of the replisome. Further, replisome progression must occur on less than ideal templates at various genomic loci. Here, we describe the functions of the major replisome components, as well as some of the obstacles to efficient DNA replication that the replisome confronts. Together, this review summarizes current understanding of the vastly complicated task of replicating eukaryotic DNA. Full article

(This article belongs to the Special Issue DNA Replication)

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