@article{MayrRamirezZavalaKruegeretal.2020,
  author    = {Mayr, Eva-Maria and Ram{\´i}rez-Zavala, Bernardo and Kr{\"u}ger, Ines and Morschh{\"a}user, Joachim},
  title     = {A Zinc Cluster Transcription Factor Contributes to the Intrinsic Fluconazole Resistance of Candida auris},
  series = {mSphere},
  volume    = {5},
  journal   = {mSphere},
  number    = {2},
  doi       = {10.1128/mSphere.00279-20},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229937},
  year      = {2020},
  abstract  = {ABSTRACT The recently emerged pathogenic yeast Candida auris is a major concern for human health, because it is easily transmissible, difficult to eradicate from hospitals, and highly drug resistant. Most C. auris isolates are resistant to the widely used antifungal drug fluconazole due to mutations in the target enzyme Erg11 and high activity of efflux pumps, such as Cdr1. In the well-studied, distantly related yeast Candida albicans, overexpression of drug efflux pumps also is a major mechanism of acquired fluconazole resistance and caused by gain-of-function mutations in the zinc cluster transcription factors Mrr1 and Tac1. In this study, we investigated a possible involvement of related transcription factors in efflux pump expression and fluconazole resistance of C. auris. The C. auris genome contains three genes encoding Mrr1 homologs and two genes encoding Tac1 homologs, and we generated deletion mutants lacking these genes in two fluconazole-resistant strains from clade III and clade IV. Deletion of TAC1b decreased the resistance to fluconazole and voriconazole in both strain backgrounds, demonstrating that the encoded transcription factor contributes to azole resistance in C. auris strains from different clades. CDR1 expression was not or only minimally affected in the mutants, indicating that Tac1b can confer increased azole resistance by a CDR1-independent mechanism. IMPORTANCE Candida auris is a recently emerged pathogenic yeast that within a few years after its initial description has spread all over the globe. C. auris is a major concern for human health, because it can cause life-threatening systemic infections, is easily transmissible, and is difficult to eradicate from hospital environments. Furthermore, C. auris is highly drug resistant, especially against the widely used antifungal drug fluconazole. Mutations in the drug target and high activity of efflux pumps are associated with azole resistance, but it is not known how drug resistance genes are regulated in C. auris. We have investigated the potential role of several candidate transcriptional regulators in the intrinsic fluconazole resistance of C. auris and identified a transcription factor that contributes to the high resistance to fluconazole and voriconazole of two C. auris strains from different genetic clades, thereby providing insight into the molecular basis of drug resistance of this medically important yeast."},
  language  = {en}
}
@article{TuChenLimetal.2012,
  author    = {Tu, Xiaolin and Chen, Jianquan and Lim, Joohyun and Karner, Courtney M. and Lee, Seung-Yon and Heisig, Julia and Wiese, Cornelia and Surendran, Kameswaran and Kopan, Raphael and Gessler, Manfred and Long, Fanxin},
  title     = {Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1},
  series = {PLoS Genetics},
  volume    = {8},
  journal   = {PLoS Genetics},
  number    = {3},
  doi       = {10.1371/journal.pgen.1002577},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133490},
  pages     = {e1002577},
  year      = {2012},
  abstract  = {Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo.},
  language  = {en}
}
@article{SzaboPapinZornetal.2013,
  author    = {Szab{\´o}, {\´A}ron and Papin, Christian and Zorn, Daniela and Ponien, Prishila and Weber, Frank and Raabe, Thomas and Rouyer, Fran{\c{c}}ois},
  title     = {The CK2 Kinase Stabilizes CLOCK and Represses Its Activity in the Drosophila Circadian Oscillator},
  series = {PLoS Biology},
  volume    = {11},
  journal   = {PLoS Biology},
  number    = {8},
  issn      = {1545-7885},
  doi       = {10.1371/journal.pbio.1001645},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127234},
  pages     = {e1001645},
  year      = {2013},
  abstract  = {Phosphorylation is a pivotal regulatory mechanism for protein stability and activity in circadian clocks regardless of their evolutionary origin. It determines the speed and strength of molecular oscillations by acting on transcriptional activators and their repressors, which form negative feedback loops. In Drosophila, the CK2 kinase phosphorylates and destabilizes the PERIOD (PER) and TIMELESS (TIM) proteins, which inhibit CLOCK (CLK) transcriptional activity. Here we show that CK2 also targets the CLK activator directly. Downregulating the activity of the catalytic alpha subunit of CK2 induces CLK degradation, even in the absence of PER and TIM. Unexpectedly, the regulatory beta subunit of the CK2 holoenzyme is not required for the regulation of CLK stability. In addition, downregulation of \(CK2\alpha\) activity decreases CLK phosphorylation and increases per and tim transcription. These results indicate that CK2 inhibits CLK degradation while reducing its activity. Since the CK1 kinase promotes CLK degradation, we suggest that CLK stability and transcriptional activity result from counteracting effects of CK1 and CK2.},
  language  = {en}
}