Transcriptional Control of the Production of Aspergillus fumigatus Conidia-Borne Secondary Metabolite Fumiquinazoline C Important for Phagocytosis Protection

Genetics ◽  
2021 ◽  
Author(s):  
Marina Campos Rocha ◽  
João Henrique Tadini Marilhano Fabri ◽  
Lilian Pereira Silva ◽  
Célio Fernando Figueiredo Angolini ◽  
Maria Célia Bertolini ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aspergillus Fumigatus ◽  
Transcriptional Control ◽  
Dual Function ◽  
Cell Physiology ◽  
Biological Functions ◽  
Environmental Niche ◽  
Peptide Synthetases ◽  
Cell Wall Integrity Pathway

Abstract Aspergillus fumigatus produces diverse secondary metabolites whose biological functions and regulation remain to be understood. Despite the importance of the conidia for this fungus, the role of the conidia-born metabolite fumiquinazoline C (FqC) is unclear. Here, we describe a dual function of the cell-wall integrity pathway in regulating FqC biosynthesis dictated by the MAPK kinase MpkA, which phosphorylates one of the nonribosomal peptide synthetases enzymes of the cluster (FmqC), and the transcription factor RlmA, which directly regulates the expression of fmq genes. Another level of crosstalk between the FqC regulation and the cell physiology is described since the deletion of the stress-responsive transcription factor sebA provokes derepression of the fmq cluster and overproduction of FqC. Thus, we describe a mechanism by which A. fumigatus controls FqC biosynthesis orchestrated by MpkA-RlmA and SebA and hence enabling survival and adaptation to the environmental niche, given that FqC is a deterrent of ameba predation.

scholarly journals Regulatory Role of microRNAs Targeting the Transcription Co-Factor ZNF521 in Normal Tissues and Cancers

2021 ◽  
Vol 22 (16) ◽  
pp. 8461
Author(s):  
Emanuela Chiarella ◽  
Annamaria Aloisio ◽  
Stefania Scicchitano ◽  
Heather Mandy Bond ◽  
Maria Mesuraca
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Transitional Cell ◽  
Biological Functions ◽  
Aberrant Expression ◽  
Normal Tissues ◽  
Novel Mirna ◽  
Mirna Expression Profiling ◽  
Mirna Deregulation

Powerful bioinformatics tools have provided a wealth of novel miRNA–transcription factor networks crucial in controlling gene regulation. In this review, we focus on the biological functions of miRNAs targeting ZNF521, explaining the molecular mechanisms by which the dysregulation of this axis contributes to malignancy. ZNF521 is a stem cell-associated co-transcription factor implicated in the regulation of hematopoietic, neural, and mesenchymal stem cells. The aberrant expression of ZNF521 transcripts, frequently associated with miRNA deregulation, has been detected in several tumors including pancreatic, hepatocellular, gastric, bladder transitional cell carcinomas as well as in breast and ovarian cancers. miRNA expression profiling tools are currently identifying a multitude of miRNAs, involved together with oncogenes and TFs in the regulation of oncogenesis, including ZNF521, which may be candidates for diagnostic and prognostic biomarkers of cancer.

Insights in the molecular mechanisms of an azole stress adapted laboratory-generated Aspergillus fumigatus strain

2021 ◽  
Author(s):  
Marion Aruanno ◽  
Samantha Gozel ◽  
Isabelle Mouyna ◽  
Josie E Parker ◽  
Daniel Bachmann ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aspergillus Fumigatus ◽  
Molecular Mechanisms ◽  
Drug Transporters ◽  
Major Facilitator Superfamily ◽  
Ergosterol Biosynthesis ◽  
Azole Resistance ◽  
Drug Transporter

Abstract Aspergillus fumigatus is the main cause of invasive aspergillosis, for which azole drugs are the first-line therapy. Emergence of pan-azole resistance among A. fumigatus is concerning and has been mainly attributed to mutations in the target gene (cyp51A). However, azole resistance may also result from other mutations (hmg1, hapE) or other adaptive mechanisms. We performed microevolution experiment exposing an A. fumigatus azole-susceptible strain (Ku80) to sub-minimal inhibitory concentration of voriconazole to analyze emergence of azole resistance. We obtained a strain with pan-azole resistance (Ku80R), which was partially reversible after drug relief, and without mutations in cyp51A, hmg1, and hapE. Transcriptomic analyses revealed overexpression of the transcription factor asg1, several ATP-binding cassette (ABC) and major facilitator superfamily transporters and genes of the ergosterol biosynthesis pathway in Ku80R. Sterol analysis showed a significant decrease of the ergosterol mass under voriconazole exposure in Ku80, but not in Ku80R. However, the proportion of the sterol compounds was similar between both strains. To further assess the role of transporters, we used the ABC transporter inhibitor milbemycine oxime (MLB). MLB inhibited transporter activity in both Ku80 and Ku80R and demonstrated some potentiating effect on azole activity. Criteria for synergism were reached for MLB and posaconazole against Ku80. Finally, deletion of asg1 revealed some role of this transcription factor in controlling drug transporter expression, but had no impact on azole susceptibility. This work provides further insight in mechanisms of azole stress adaptation and suggests that drug transporters inhibition may represent a novel therapeutic target. Lay Summary A pan-azole-resistant strain was generated in vitro, in which drug transporter overexpression was a major trait. Analyses suggested a role of the transporter inhibitor milbemycin oxime in inhibiting drug transporters and potentiating azole activity.

Transcriptional control of human papillomavirus type 18 oncogene expression in different cell lines: Role of transcription factor YY1

Virus Genes ◽  
1995 ◽  
Vol 11 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Franziska Jundt ◽  
Ingrid Herr ◽  
Peter Angel ◽  
Harald Zur Hausen ◽  
Tobias Bauknecht
Keyword(s):  
Transcription Factor ◽  
Human Papillomavirus ◽  
Cell Lines ◽  
Transcriptional Control ◽  
Oncogene Expression ◽  
Transcription Factor Yy1

scholarly journals The Expanding Role of MT1-MMP in Cancer Progression

2019 ◽  
Vol 12 (2) ◽  
pp. 77 ◽  
Author(s):  
Anna M. Knapinska ◽  
Gregg B. Fields
Keyword(s):  
Transcription Factor ◽  
Immune Responses ◽  
Cancer Progression ◽  
Negative Regulator ◽  
Fibrillar Collagen ◽  
Biological Functions ◽  
Complete Mapping ◽  
Membrane Type

For over 20 years, membrane type 1 matrix metalloproteinase (MT1-MMP) has been recognized as a key component in cancer progression. Initially, the primary roles assigned to MT1-MMP were the activation of proMMP-2 and degradation of fibrillar collagen. Proteomics has revealed a great array of MT1-MMP substrates, and MT1-MMP selective inhibitors have allowed for a more complete mapping of MT1-MMP biological functions. MT1-MMP has extensive sheddase activities, is both a positive and negative regulator of angiogenesis, can act intracellularly and as a transcription factor, and modulates immune responses. We presently examine the multi-faceted role of MT1-MMP in cancer, with a consideration of how the diversity of MT1-MMP behaviors impacts the application of MT1-MMP inhibitors.

scholarly journals TIP49b, a Regulator of Activating Transcription Factor 2 Response to Stress and DNA Damage

2001 ◽  
Vol 21 (24) ◽  
pp. 8398-8413 ◽  
Author(s):  
Ssang-Goo Cho ◽  
Anindita Bhoumik ◽  
Limor Broday ◽  
Vladimir Ivanov ◽  
Barry Rosenstein ◽  
...  
Keyword(s):  
Dna Damage ◽  
Transcription Factor ◽  
Transcriptional Control ◽  
Constitutive Expression ◽  
Normal Growth ◽  
Growth Conditions ◽  
Interacting Protein ◽  
Response To Stress ◽  
Activating Transcription Factor

ABSTRACT Activating transcription factor 2 (ATF2/CRE-BP1) is implicated in transcriptional control of stress-responsive genes. A yeast two-hybrid screen identified TBP-interacting protein 49b (TIP49b), a component of the INO80 chromatin-remodeling complex, as a novel ATF2-interacting protein. TIP49b's association with ATF2 is phosphorylation dependent and requires amino acids 150 to 248 of ATF2 (ATF2150–248), which are implicated in intramolecular inhibition of ATF2 transcriptional activities. Forced expression of TIP49b efficiently attenuated ATF2 transcriptional activities under normal growth conditions as well as after UV treatment, ionizing irradiation, or activation of p38 kinase, all of which induced ATF2 phosphorylation and increased TIP49b-ATF2 association. Constitutive expression of ATF2150–248 peptide outcompeted TIP49b interaction with ATF2 and alleviated the suppression of ATF2 transcriptional activities. Expression of ATF2150–248 in fibroblasts or melanoma but not in ATF2-null cells caused a profound G2M arrest and increased degree of apoptosis following irradiation. The interaction between ATF2 and TIP49b constitutes a novel mechanism that serves to limit ATF2 transcriptional activities and highlights the central role of ATF2 in the control of the cell cycle and apoptosis in response to stress and DNA damage.

scholarly journals Novel Biological Functions of the NsdC Transcription Factor in Aspergillus fumigatus

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Patrícia Alves de Castro ◽  
Clara Valero ◽  
Jéssica Chiaratto ◽  
Ana Cristina Colabardini ◽  
Lakhansing Pardeshi ◽  
...  
Keyword(s):  
Cell Wall ◽  
Transcription Factor ◽  
Aspergillus Fumigatus ◽  
Sexual Reproduction ◽  
Rna Polymerase Ii ◽  
Vegetative Growth ◽  
Wall Structure ◽  
Immune Recognition ◽  
Biological Functions ◽  
Content Type

ABSTRACT The fungal zinc finger transcription factor NsdC is named after, and is best known for, its essential role in sexual reproduction (never in sexual development). In previous studies with Aspergillus nidulans, it was also shown to have roles in promotion of vegetative growth and suppression of asexual conidiation. In this study, the function of the nsdC homologue in the opportunistic human pathogen A. fumigatus was investigated. NsdC was again found to be essential for sexual development, with deletion of the nsdC gene in both MAT1-1 and MAT1-2 mating partners of a cross leading to complete loss of fertility. However, a functional copy of nsdC in one mating partner was sufficient to allow sexual reproduction. Deletion of nsdC also led to decreased vegetative growth and allowed conidiation in liquid cultures, again consistent with previous findings. However, NsdC in A. fumigatus was shown to have additional biological functions including response to calcium stress, correct organization of cell wall structure, and response to the cell wall stressors. Furthermore, virulence and host immune recognition were affected. Gene expression studies involving chromatin immunoprecipitation (ChIP) of RNA polymerase II (PolII) coupled to next-generation sequencing (Seq) revealed that deletion of nsdC resulted in changes in expression of over 620 genes under basal growth conditions. This demonstrated that this transcription factor mediates the activity of a wide variety of signaling and metabolic pathways and indicates that despite the naming of the gene, the promotion of sexual reproduction is just one among multiple roles of NsdC. IMPORTANCE Aspergillus fumigatus is an opportunistic human fungal pathogen and the main causal agent of invasive aspergillosis, a life-threatening infection especially in immunocompromised patients. A. fumigatus can undergo both asexual and sexual reproductive cycles, and the regulation of both cycles involves several genes and pathways. Here, we have characterized one of these genetic determinants, the NsdC transcription factor, which was initially identified in a screen of transcription factor null mutants showing sensitivity when exposed to high concentrations of calcium. In addition to its known essential roles in sexual reproduction and control of growth rate and asexual reproduction, we have shown in the present study that A. fumigatus NsdC transcription factor has additional previously unrecognized biological functions including calcium tolerance, cell wall stress response, and correct cell wall organization and functions in virulence and host immune recognition. Our results indicate that NsdC can play novel additional biological functions not directly related to its role played during sexual and asexual processes.

Role of Swi4 in cell cycle regulation of CLN2 expression

1994 ◽  
Vol 14 (7) ◽  
pp. 4779-4787
Author(s):  
F R Cross ◽  
M Hoek ◽  
J D McKinney ◽  
A H Tinkelenberg
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Restriction Fragment ◽  
Positive Feedback ◽  
Cell Cycle Regulation ◽  
Transcriptional Control ◽  
Regulatory Factors ◽  
Cycle Regulation

Expression of the Saccharomyces cerevisiae CLN1 and CLN2 genes is cell cycle regulated, and the genes may be controlled by positive feedback. It has been proposed that positive feedback operates via Cln/Cdc28 activation of the Swi4/Swi6 transcription factor, leading to CLN1 and CLN2 transcription due to Swi4 binding to specific sites (SCBs) in the CLN1 and CLN2 promoters. To test this proposal, we have examined the effects of deletion either of the potential SCBs in the CLN2 promoter or of the SWI4 gene on CLN2 transcriptional control. Deletion of a restriction fragment containing the identified SCBs from the promoter does not prevent cell cycle regulation of CLN2 expression, although expression is lowered at all cell cycle positions. A promoter containing a 5.5-kb plasmid insertion or an independent 2.5-kb insertion at the point of deletion of the SCB-containing restriction fragment also exhibits cell cycle regulation, so involvement of unidentified upstream SCBs is unlikely. Neither Swi4 nor the related Mbp1 transcription factor is required for cell cycle regulation of the intact CLN2 promoter. In contrast, Swi4 (but not Mbp1) is required for correct cell cycle regulation of the insertion/deletion promoter lacking SCB sites. We have extended previous genetic evidence for involvement of Swi4 in some aspect of CLN2 function: a mutant hunt for CLN2 positive regulatory factors yielded only swi4 mutations at saturation. Swi4 may bind to nonconsensus sequences in the CLN2 promoter (possibly in addition to consensus sites), or it may act indirectly to regulate CLN2 expression.

scholarly journals Role of Swi4 in cell cycle regulation of CLN2 expression.

1994 ◽  
Vol 14 (7) ◽  
pp. 4779-4787 ◽  
Author(s):  
F R Cross ◽  
M Hoek ◽  
J D McKinney ◽  
A H Tinkelenberg
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Restriction Fragment ◽  
Positive Feedback ◽  
Cell Cycle Regulation ◽  
Transcriptional Control ◽  
Regulatory Factors ◽  
Cycle Regulation

Expression of the Saccharomyces cerevisiae CLN1 and CLN2 genes is cell cycle regulated, and the genes may be controlled by positive feedback. It has been proposed that positive feedback operates via Cln/Cdc28 activation of the Swi4/Swi6 transcription factor, leading to CLN1 and CLN2 transcription due to Swi4 binding to specific sites (SCBs) in the CLN1 and CLN2 promoters. To test this proposal, we have examined the effects of deletion either of the potential SCBs in the CLN2 promoter or of the SWI4 gene on CLN2 transcriptional control. Deletion of a restriction fragment containing the identified SCBs from the promoter does not prevent cell cycle regulation of CLN2 expression, although expression is lowered at all cell cycle positions. A promoter containing a 5.5-kb plasmid insertion or an independent 2.5-kb insertion at the point of deletion of the SCB-containing restriction fragment also exhibits cell cycle regulation, so involvement of unidentified upstream SCBs is unlikely. Neither Swi4 nor the related Mbp1 transcription factor is required for cell cycle regulation of the intact CLN2 promoter. In contrast, Swi4 (but not Mbp1) is required for correct cell cycle regulation of the insertion/deletion promoter lacking SCB sites. We have extended previous genetic evidence for involvement of Swi4 in some aspect of CLN2 function: a mutant hunt for CLN2 positive regulatory factors yielded only swi4 mutations at saturation. Swi4 may bind to nonconsensus sequences in the CLN2 promoter (possibly in addition to consensus sites), or it may act indirectly to regulate CLN2 expression.

scholarly journals Transcription Factor PrtT Controls Expression of Multiple Secreted Proteases in the Human Pathogenic Mold Aspergillus fumigatus

2009 ◽  
Vol 77 (9) ◽  
pp. 4051-4060 ◽  
Author(s):  
Haim Sharon ◽  
Shelly Hagag ◽  
Nir Osherov
Keyword(s):  
Transcription Factor ◽  
Aspergillus Niger ◽  
Aspergillus Fumigatus ◽  
Deletion Mutant ◽  
Pathogenic Fungus ◽  
Lung Epithelial Cells ◽  
Deletion Strain ◽  
Lung Epithelial ◽  
Secreted Proteases

ABSTRACT The role of secreted proteases in the virulence of the pathogenic fungus Aspergillus fumigatus remains controversial. Recently, the Aspergillus niger transcription factor PrtT was shown to control the expression of multiple secreted proteases. In this work, the gene which encodes the PrtT homolog in A. fumigatus was cloned and its function analyzed using a deletion mutant strain. Deletion of A. fumigatus prtT resulted in the loss of secreted protease activity. The expression of six secreted proteases (ALP, MEP, Dpp4, CpdS, AFUA_2G17330, and AFUA_7G06220) was markedly reduced. Culture filtrates from the prtT deletion strain exhibited reduced killing of lung epithelial cells and lysis of erythrocytes. However, the prtT deletion strain did not exhibit altered virulence in lung-infected mice. These results suggest that PrtT is not a significant virulence factor in A. fumigatus.

scholarly journals Transcriptional Control of Synaptic Plasticity by Transcription Factor NF-κB

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Christian Engelmann ◽  
Ronny Haenold
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Synaptic Plasticity ◽  
Transcriptional Control ◽  
Memory Formation ◽  
Inhibitory Synapses ◽  
Cross Sectional ◽  
Learning Deficits ◽  
Altered Gene

Activation of nuclear factor kappa B (NF-κB) transcription factors is required for the induction of synaptic plasticity and memory formation. All components of this signaling pathway are localized at synapses, and transcriptionally active NF-κB dimers move to the nucleus to translate synaptic signals into altered gene expression. Neuron-specific inhibition results in altered connectivity of excitatory and inhibitory synapses and functionally in selective learning deficits. Recent research on transgenic mice with impaired or hyperactivated NF-κB gave important insights into plasticity-related target gene expression that is regulated by NF-κB. In this minireview, we update the available data on the role of this transcription factor for learning and memory formation and comment on cross-sectional activation of NF-κB in the aged and diseased brain that may directly or indirectly affectκB-dependent transcription of synaptic genes.

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