scholarly journals BRN2 is a non-canonical melanoma tumor-suppressor

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Michael Hamm ◽  
Pierre Sohier ◽  
Valérie Petit ◽  
Jérémy H. Raymond ◽  
Véronique Delmas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Tumor Suppressor ◽  
The Other ◽  
Pi3k Signaling ◽  
Melanoma Tumor ◽  
Temporal Regulation ◽  
Metastatic Colonization ◽  
Pou Domain

AbstractWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600EPtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.

scholarly journals BRN2 is a non-canonical melanoma tumor-suppressor

2021 ◽  
Author(s):  
Michael Hamm ◽  
Pierre Sohier ◽  
Valérie Petit ◽  
Jérémy H Raymond ◽  
Véronique Delmas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Tumor Suppressor ◽  
Molecular Mechanisms ◽  
Human Melanoma ◽  
Allelic Loss ◽  
Pi3k Signaling ◽  
Tumor Initiation ◽  
Melanoma Tumor

ABSTRACTWhile the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, we show that BRN2 haplo-insufficiency is sufficient to promote melanoma initiation and metastasis, acting as a non-canonical tumor suppressor. Mechanistically, BRN2 directly modulates PTEN expression, and PI3K signaling, to drive tumor initiation and progression. Collectively our results reveal that somatic deletion of one BRN2 allele elicits melanoma initiation and progression.SIGNIFICANCEHere, we report frequent mono-allelic loss of the transcription factor BRN2 in human cutaneous melanoma metastases. We developed a mouse model for Brn2-deficient melanoma based on the most common alterations (BrafV600E and Pten loss) in human melanoma and established the role of Brn2 as a functional regulator of tumor initiation, tumor growth, and the formation of metastases in vivo. Mechanistically, BRN2 loss increases PI3K-signaling through PTEN repression, either via MITF induction or not. Overall, we describe a novel tumor suppressor of high prevalence in human melanoma that regulates several steps of in vivo melanomagenesis through two previously unknown molecular mechanisms.

scholarly journals A Novel cis Element Achieves the Same Solution as an Ancestral cis Element During Thiamine Starvation in Candida glabrata

2019 ◽  
Vol 10 (1) ◽  
pp. 321-331 ◽  
Author(s):  
Christine L. Iosue ◽  
Anthony P. Gulotta ◽  
Kathleen B. Selhorst ◽  
Alison C. Mody ◽  
Kristin M. Barbour ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Site ◽  
Candida Glabrata ◽  
Regulatory Networks ◽  
The Other ◽  
Factor Binding Site ◽  
Cis Element ◽  
Element Evolution

Regulatory networks often converge on very similar cis sequences to drive transcriptional programs due to constraints on what transcription factors are present. To determine the role of constraint loss on cis element evolution, we examined the recent appearance of a thiamine starvation regulated promoter in Candida glabrata. This species lacks the ancestral transcription factor Thi2, but still has the transcription factor Pdc2, which regulates thiamine starvation genes, allowing us to determine the effect of constraint change on a new promoter. We identified two different cis elements in C. glabrata - one present in the evolutionarily recent gene called CgPMU3, and the other element present in the other thiamine (THI) regulated genes. Reciprocal swaps of the cis elements and incorporation of the S. cerevisiaeThi2 transcription factor-binding site into these promoters demonstrate that the two elements are functionally different from one another. Thus, this loss of an imposed constraint on promoter function has generated a novel cis sequence, suggesting that loss of trans constraints can generate a non-convergent pathway with the same output.

scholarly journals HbxB Is a Key Regulator for Stress Response and β-Glucan Biogenesis in Aspergillus nidulans

2021 ◽  
Vol 9 (1) ◽  
pp. 144
Author(s):  
Sung-Hun Son ◽  
Mi-Kyung Lee ◽  
Ye-Eun Son ◽  
Hee-Soo Park
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Aspergillus Nidulans ◽  
Deletion Mutant ◽  
Phenotypic Analysis ◽  
Spore Viability ◽  
Fungal Development ◽  
Expression Of Genes ◽  
Trehalose Biosynthesis

Homeobox transcription factors are conserved in eukaryotes and act as multi-functional transcription factors in filamentous fungi. Previously, it was demonstrated that HbxB governs fungal development and spore viability in Aspergillus nidulans. Here, the role of HbxB in A. nidulans was further characterized. RNA-sequencing revealed that HbxB affects the transcriptomic levels of genes associated with trehalose biosynthesis and response to thermal, oxidative, and radiation stresses in asexual spores called conidia. A phenotypic analysis found that hbxB deletion mutant conidia were more sensitive to ultraviolet stress. The loss of hbxB increased the mRNA expression of genes associated with β-glucan degradation and decreased the amount of β-glucan in conidia. In addition, hbxB deletion affected the expression of the sterigmatocystin gene cluster and the amount of sterigmatocystin. Overall, these results indicated that HbxB is a key transcription factor regulating trehalose biosynthesis, stress tolerance, β-glucan degradation, and sterigmatocystin production in A.nidulans conidia.

scholarly journals How cancer cells remodel lipid metabolism: strategies targeting transcription factors

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Do-Won Jeong ◽  
Seulbee Lee ◽  
Yang-Sook Chun
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Lipid Metabolism ◽  
Cancer Cells ◽  
Cancer Biology ◽  
Factors Associated ◽  
Modeling Techniques ◽  
Related Enzyme ◽  
Potential Strategy

AbstractReprogramming of lipid metabolism has received increasing recognition as a hallmark of cancer cells because lipid dysregulation and the alteration of related enzyme profiles are closely correlated with oncogenic signals and malignant phenotypes, such as metastasis and therapeutic resistance. In this review, we describe recent findings that support the importance of lipids, as well as the transcription factors involved in cancer lipid metabolism. With recent advances in transcription factor analysis, including computer-modeling techniques, transcription factors are emerging as central players in cancer biology. Considering the limited number and the crucial role of transcription factors associated with lipid rewiring in cancers, transcription factor targeting is a promising potential strategy for cancer therapy.

scholarly journals Is the Secret of VDAC Isoforms in Their Gene Regulation? Characterization of Human VDAC Genes Expression Profile, Promoter Activity, and Transcriptional Regulators

2020 ◽  
Vol 21 (19) ◽  
pp. 7388
Author(s):  
Federica Zinghirino ◽  
Xena Giada Pappalardo ◽  
Angela Messina ◽  
Francesca Guarino ◽  
Vito De Pinto
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Promoter Activity ◽  
Expression Profiles ◽  
Transcriptional Regulators ◽  
General Role ◽  
Nuclear Respiratory Factor ◽  
Nuclear Respiratory Factor 1

VDACs (voltage-dependent anion-selective channels) are pore-forming proteins of the outer mitochondrial membrane, whose permeability is primarily due to VDACs’ presence. In higher eukaryotes, three isoforms are raised during the evolution: they have the same exon–intron organization, and the proteins show the same channel-forming activity. We provide a comprehensive analysis of the three human VDAC genes (VDAC1–3), their expression profiles, promoter activity, and potential transcriptional regulators. VDAC isoforms are broadly but also specifically expressed in various human tissues at different levels, with a predominance of VDAC1 and VDAC2 over VDAC3. However, an RNA-seq cap analysis gene expression (CAGE) approach revealed a higher level of transcription activation of VDAC3 gene. We experimentally confirmed this information by reporter assay of VDACs promoter activity. Transcription factor binding sites (TFBSs) distribution in the promoters were investigated. The main regulators common to the three VDAC genes were identified as E2F-myc activator/cell cycle (E2FF), Nuclear respiratory factor 1 (NRF1), Krueppel-like transcription factors (KLFS), E-box binding factors (EBOX) transcription factor family members. All of them are involved in cell cycle and growth, proliferation, differentiation, apoptosis, and metabolism. More transcription factors specific for each VDAC gene isoform were identified, supporting the results in the literature, indicating a general role of VDAC1, as an actor of apoptosis for VDAC2, and the involvement in sex determination and development of VDAC3. For the first time, we propose a comparative analysis of human VDAC promoters to investigate their specific biological functions. Bioinformatics and experimental results confirm the essential role of the VDAC protein family in mitochondrial functionality. Moreover, insights about a specialized function and different regulation mechanisms arise for the three isoform gene.

scholarly journals Role of DBP in the Circadian Oscillatory Mechanism

2000 ◽  
Vol 20 (13) ◽  
pp. 4773-4781 ◽  
Author(s):  
Shun Yamaguchi ◽  
Shigeru Mitsui ◽  
Lily Yan ◽  
Kazuhiro Yagita ◽  
Shigeru Miyake ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Leucine Zipper ◽  
The Other ◽  
Suprachiasmatic Nuclei ◽  
Transcription Factor Family ◽  
Transcript Levels ◽  
Oscillatory Mechanism ◽  
Central Clock ◽  
E Boxes

ABSTRACT Transcript levels of DBP, a member of the PAR leucine zipper transcription factor family, exhibit a robust rhythm in suprachiasmatic nuclei, the mammalian circadian center. Here we report that DBP is able to activate the promoter of a putative clock oscillating gene,mPer1, by directly binding to the mPer1promoter. The mPer1 promoter is cooperatively activated by DBP and CLOCK-BMAL1. On the other hand, dbp transcription is activated by CLOCK-BMAL1 through E-boxes and inhibited by the mPER and mCRY proteins, as is the case for mPer1. Thus, a clock-controlled dbp gene may play an important role in central clock oscillation.

scholarly journals POU domain transcription factor brain 4 confers pancreatic alpha-cell-specific expression of the proglucagon gene through interaction with a novel proximal promoter G1 element.

1997 ◽  
Vol 17 (12) ◽  
pp. 7186-7194 ◽  
Author(s):  
M A Hussain ◽  
J Lee ◽  
C P Miller ◽  
J F Habener
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Alpha Cell ◽  
Proximal Promoter ◽  
Major Constituent ◽  
Alpha Cells ◽  
Specific Expression ◽  
Pou Domain ◽  
Pancreatic Alpha Cell

The proglucagon gene is expressed in a highly restricted tissue-specific manner in the alpha cells of the pancreatic islet, the hypothalamus, and the small and large intestines. Proglucagon is processed to glucagon and glucagon-like peptides GLP-1 and -2. Glucagon is expressed in alpha cells and regulates glucose homeostasis. GLP-1 is implicated in the control of insulin secretion, food intake, and satiety signaling, and GLP-2 is implicated in regulating small-bowel growth. Cell-specific expression of the proglucagon gene is mediated by proteins that interact with the proximal G1 promoter element which contains several AT-rich domains with binding sites for homeodomain transcription factors. In an attempt to identify major homeodomain proteins involved in pancreatic alpha-cell-specific proglucagon expression, we found that the POU domain transcription factor brain 4 is abundantly expressed in proglucagon-producing islet cell lines and rat pancreatic islets. In the latter, brain 4 and glucagon immunoreactivity colocalize in the outer mantle of islets. Electrophoretic mobility shift assays with specific antisera identify brain 4 as a major constituent of nuclear proteins of glucagon-producing cells that bind to the G1 element of the proglucagon gene proximal promoter. Transcriptional transactivation experiments reveal that brain 4 is a major regulator of proglucagon gene expression by its interaction with the G1 element. The finding that a neuronal transcription factor is involved in glucagon gene transcription may explain the presence of proglucagon in certain areas of the brain as well as in pancreatic alpha cells. Further, this finding supports the idea that the neuronal properties of endodermis-derived endocrine pancreatic cells may find their basis in regulation of gene expression by neuronal transcription factors.

scholarly journals AP1 Transcription Factors in Epidermal Differentiation and Skin Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Richard L. Eckert ◽  
Gautam Adhikary ◽  
Christina A. Young ◽  
Ralph Jans ◽  
James F. Crish ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Dominant Negative ◽  
Epidermal Differentiation ◽  
Cancer Development ◽  
Multiple Cells ◽  
Different Levels ◽  
Factor Function

AP1 (jun/fos) transcription factors (c-jun, junB, junD, c-fos, FosB, Fra-1, and Fra-2) are key regulators of epidermal keratinocyte survival and differentiation and important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each protein is expressed, at different levels, in multiple cells layers in differentiating epidermis, and because AP1 transcription factors regulate competing processes (i.e., proliferation, apoptosis, and differentiation). Variousin vivogenetic approaches have been used to study these proteins including targeted and conditional knockdown, overexpression, and expression of dominant-negative inactivating AP1 transcription factors in epidermis. Taken together, these studies suggest that individual AP1 transcription factors have different functions in the epidermis and in cancer development and that altering AP1 transcription factor function in the basal versus suprabasal layers differentially influences the epidermal differentiation response and disease and cancer development.

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