RFX1: a promising therapeutic arsenal against cancer

AbstractRegulatory factor X1 (RFX1) is an evolutionary conserved transcriptional factor that influences a wide range of cellular processes such as cell cycle, cell proliferation, differentiation, and apoptosis, by regulating a number of target genes that are involved in such processes. On a closer look, these target genes also play a key role in tumorigenesis and associated events. Such observations paved the way for further studies evaluating the role of RFX1 in cancer. These studies were indispensable due to the failure of conventional chemotherapeutic drugs to target key cellular hallmarks such as cancer stemness, cellular plasticity, enhanced drug efflux, de-regulated DNA repair machinery, and altered pathways evading apoptosis. In this review, we compile significant evidence for the tumor-suppressive activities of RFX1 while also analyzing its oncogenic potential in some cancers. RFX1 induction decreased cellular proliferation, modulated the immune system, induced apoptosis, reduced chemoresistance, and sensitized cancer stem cells for chemotherapy. Thus, our review discusses the pleiotropic function of RFX1 in multitudinous gene regulations, decisive protein–protein interactions, and also its role in regulating key cell signaling events in cancer. Elucidation of these regulatory mechanisms can be further utilized for RFX1 targeted therapy.

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Ways into Understanding HIF Inhibition

Cancers ◽

10.3390/cancers13010159 ◽

2021 ◽

Vol 13 (1) ◽

pp. 159

Author(s):

Tina Schönberger ◽

Joachim Fandrey ◽

Katrin Prost-Fingerle

Keyword(s):

Protein Interactions ◽

Target Genes ◽

Protein Protein Interactions ◽

Low Oxygen ◽

Drug Candidates ◽

Open Questions ◽

Wide Range ◽

Hif Pathway

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds.

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Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Current Medicinal Chemistry ◽

10.2174/0929867324666170426095015 ◽

2018 ◽

Vol 25 (1) ◽

pp. 5-21 ◽

Cited By ~ 25

Author(s):

Ylenia Cau ◽

Daniela Valensin ◽

Mattia Mori ◽

Sara Draghi ◽

Maurizio Botta

Keyword(s):

Protein Interactions ◽

Molecular Mechanisms ◽

Physiological Role ◽

Specific Protein ◽

Protein Protein Interactions ◽

Cellular Processes ◽

Protein Partners ◽

High Sequence Homology ◽

Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

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The interaction of IQGAPs with calmodulin-like proteins

Biochemical Society Transactions ◽

10.1042/bst0390694 ◽

2011 ◽

Vol 39 (2) ◽

pp. 694-699 ◽

Cited By ~ 13

Author(s):

Sevvel Pathmanathan ◽

Elaine Hamilton ◽

Erwan Atcheson ◽

David J. Timson

Keyword(s):

Protein Interactions ◽

Light Chain ◽

Protein Protein Interactions ◽

Iq Motif ◽

Calcium Dependent ◽

Essential Light Chain ◽

Cellular Processes ◽

Wide Range ◽

Related Proteins ◽

Do So

Since their identification over 15 years ago, the IQGAP (IQ-motif-containing GTPase-activating protein) family of proteins have been implicated in a wide range of cellular processes, including cytoskeletal reorganization, cell–cell adhesion, cytokinesis and apoptosis. These processes rely on protein–protein interactions, and understanding these (and how they influence one another) is critical in determining how the IQGAPs function. A key group of interactions is with calmodulin and the structurally related proteins myosin essential light chain and S100B. These interactions occur primarily through a series of IQ motifs, which are α-helical segments of the protein located towards the middle of the primary sequence. The three human IQGAP isoforms (IQGAP1, IQGAP2 and IQGAP3) all have four IQ motifs. However, these have different affinities for calmodulin, myosin light chain and S100B. Whereas all four IQ motifs of IQGAP1 interact with calmodulin in the presence of calcium, only the last two do so in the absence of calcium. IQ1 (the first IQ motif) interacts with the myosin essential light chain Mlc1sa and the first two undergo a calcium-dependent interaction with S100B. The significance of the interaction between Mlc1sa and IQGAP1 in mammals is unknown. However, a similar interaction involving the Saccharomyces cerevisiae IQGAP-like protein Iqg1p is involved in cytokinesis, leading to speculation that there may be a similar role in mammals.

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Proteins-partners of PH domain of BCR-ABL protein: creation of DNA constructs to uncover molecular characteristics of CML development

Faktori eksperimental'noi evolucii organizmiv ◽

10.7124/feeo.v20.732 ◽

1970 ◽

pp. 47-52

Author(s):

S. V. Antonenko ◽

I. V. Kravchuk ◽

D. S. Gurianov ◽

G. D. Telegeev

Keyword(s):

Protein Interactions ◽

Coli Strain ◽

Molecular Characteristics ◽

Ph Domain ◽

Protein Protein Interactions ◽

E Coli ◽

Cellular Processes ◽

Molecular Events ◽

Genetic Constructs

Aim. Impact of domains of Bcr in oncogenic effect associated with Bcr-Abl remains unclear. Investigation of protein-protein interactions can be one of the effective ways to reveal those molecular events that alter normal cellular processes and cause malignant transformation. Previous research showed that USP1, Cortactin and Hsp27 may interact with PH domain. To confirm interactions and to study their biological consequences, genetic constructs for expression and microscopy should be created. Methods. Various standard molecular cloning techniques and expression in E. coli strain Rosetta. Results. Several DNA constructs have been created (pBluescriptSKII(+)+USP1, pFastFT-N1-CTTN, pMediumFT-N1-CTTN, pSlowFT-N1- CTTN and pET42a-hsp27). Effective bacterial expression of Hsp27 has been performed. Conclusions. All DNA constructs can be effective instruments to study biological role of interactions between PH domain of Bcr and USP1, Cortactin, Hsp27.Keywords: PH domain, Bcr-Abl, USP1, Cortactin, Hsp27.

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Identification of 56 Proteins Involved in Embryo–Maternal Interactions in the Bovine Oviduct

International Journal of Molecular Sciences ◽

10.3390/ijms21020466 ◽

2020 ◽

Vol 21 (2) ◽

pp. 466 ◽

Cited By ~ 5

Author(s):

Charles Banliat ◽

Guillaume Tsikis ◽

Valérie Labas ◽

Ana-Paula Teixeira-Gomes ◽

Emmanuelle Com ◽

...

Keyword(s):

Protein Interactions ◽

High Resolution Mass Spectrometry ◽

Bovine Embryo ◽

Interacting Proteins ◽

Cellular Processes ◽

Wide Range ◽

Range Of Functions ◽

First Time

The bovine embryo develops in contact with the oviductal fluid (OF) during the first 4–5 days of pregnancy. The aim of this study was to decipher the protein interactions occurring between the developing embryo and surrounding OF. In-vitro produced 4–6 cell and morula embryos were incubated or not (controls) in post-ovulatory OF (OF-treated embryos) and proteins were then analyzed and quantified by high resolution mass spectrometry (MS) in both embryo groups and in OF. A comparative analysis of MS data allowed the identification and quantification of 56 embryo-interacting proteins originated from the OF, including oviductin (OVGP1) and several annexins (ANXA1, ANXA2, ANXA4) as the most abundant ones. Some embryo-interacting proteins were developmental stage-specific, showing a modulating role of the embryo in protein interactions. Three interacting proteins (OVGP1, ANXA1 and PYGL) were immunolocalized in the perivitelline space and in blastomeres, showing that OF proteins were able to cross the zona pellucida and be taken up by the embryo. Interacting proteins were involved in a wide range of functions, among which metabolism and cellular processes were predominant. This study identified for the first time a high number of oviductal embryo-interacting proteins, paving the way for further targeted studies of proteins potentially involved in the establishment of pregnancy in cattle.

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Histone H3K4 Methyltransferases as Targets for Drug-Resistant Cancers

Biology ◽

10.3390/biology10070581 ◽

2021 ◽

Vol 10 (7) ◽

pp. 581

Author(s):

Liu Yang ◽

Mingli Jin ◽

Kwang Won Jeong

Keyword(s):

Drug Resistance ◽

Protein Interactions ◽

Target Genes ◽

Triple Negative ◽

Castration Resistant Prostate Cancer ◽

Protein Protein Interactions ◽

Castration Resistant ◽

Histone H3k4 ◽

H3k4 Methyltransferases

The KMT2 (MLL) family of proteins, including the major histone H3K4 methyltransferase found in mammals, exists as large complexes with common subunit proteins and exhibits enzymatic activity. SMYD, another H3K4 methyltransferase, and SET7/9 proteins catalyze the methylation of several non-histone targets, in addition to histone H3K4 residues. Despite these structural and functional commonalities, H3K4 methyltransferase proteins have specificity for their target genes and play a role in the development of various cancers as well as in drug resistance. In this review, we examine the overall role of histone H3K4 methyltransferase in the development of various cancers and in the progression of drug resistance. Compounds that inhibit protein–protein interactions between KMT2 family proteins and their common subunits or the activity of SMYD and SET7/9 are continuously being developed for the treatment of acute leukemia, triple-negative breast cancer, and castration-resistant prostate cancer. These H3K4 methyltransferase inhibitors, either alone or in combination with other drugs, are expected to play a role in overcoming drug resistance in leukemia and various solid cancers.

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MicroRNAs: crucial regulators of placental development

Reproduction ◽

10.1530/rep-17-0603 ◽

2018 ◽

Vol 155 (6) ◽

pp. R259-R271 ◽

Cited By ~ 38

Author(s):

Heyam Hayder ◽

Jacob O’Brien ◽

Uzma Nadeem ◽

Chun Peng

Keyword(s):

Mrna Stability ◽

Target Genes ◽

Current Knowledge ◽

Mirna Biogenesis ◽

Placental Development ◽

Future Directions ◽

Cellular Processes ◽

Wide Range ◽

Canonical Pathways

MicroRNAs (miRNAs) are small non-coding single-stranded RNAs that are integral to a wide range of cellular processes mainly through the regulation of translation and mRNA stability of their target genes. The placenta is a transient organ that exists throughout gestation in mammals, facilitating nutrient and gas exchange and waste removal between the mother and the fetus. miRNAs are expressed in the placenta, and many studies have shown that miRNAs play an important role in regulating trophoblast differentiation, migration, invasion, proliferation, apoptosis, vasculogenesis/angiogenesis and cellular metabolism. In this review, we provide a brief overview of canonical and non-canonical pathways of miRNA biogenesis and mechanisms of miRNA actions. We highlight the current knowledge of the role of miRNAs in placental development. Finally, we point out several limitations of the current research and suggest future directions.

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SUMOylation of the Corepressor N-CoR Modulates Its Capacity to Repress Transcription

Molecular Biology of the Cell ◽

10.1091/mbc.e05-07-0610 ◽

2006 ◽

Vol 17 (4) ◽

pp. 1643-1651 ◽

Cited By ~ 39

Author(s):

Jens Tiefenbach ◽

Natalia Novac ◽

Miryam Ducasse ◽

Maresa Eck ◽

Frauke Melchior ◽

...

Keyword(s):

Protein Interactions ◽

Posttranslational Modifications ◽

Transcriptional Repression ◽

Histone Deacetylases ◽

Hormone Receptors ◽

Target Genes ◽

Protein Protein Interactions ◽

Lysine Residues

In the absence of ligands the corepressor N-CoR mediates transcriptional repression by some nuclear hormone receptors. Several protein–protein interactions of N-CoR are known, of which mainly complex formation with histone deacetylases (HDACs) leads to the repression of target genes. On the other hand, the role of posttranslational modifications in corepressor function is not well established. Here, we show that N-CoR is modified by Sumo-1. We found SUMO-E2–conjugating enzyme Ubc9 and SUMO-E3 ligase Pias1 as novel N-CoR interaction partners. The SANT1 domain of N-CoR was found to mediate this interaction. We show that K152, K1117, and K1330 of N-CoR can be conjugated to SUMO and that mutation of all sites is necessary to fully block SUMOylation in vitro. Because these lysine residues are located within repression domains I and III, respectively, we investigated a possible correlation between the functions of the repression domains and SUMOylation. Coexpression of Ubc9 protein resulted in enhanced N-CoR–dependent transcriptional repression. Studies using SUMOylation-deficient N-CoR RDI mutants suggest that SUMO modification contributes to repression by N-CoR. Mutation of K152 to R in RD1, for example, not only significantly reduced repression of a reporter gene, but also abolished the effect of Ubc9 on transcriptional repression.

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The role of miRNAs in regulating adrenal and gonadal steroidogenesis

Journal of Molecular Endocrinology ◽

10.1530/jme-19-0105 ◽

2020 ◽

Vol 64 (1) ◽

pp. R21-R43 ◽

Cited By ~ 3

Author(s):

Salman Azhar ◽

Dachuan Dong ◽

Wen-Jun Shen ◽

Zhigang Hu ◽

Fredric B Kraemer

Keyword(s):

Cardiovascular Diseases ◽

Protein Interactions ◽

Small Rnas ◽

Target Genes ◽

Metabolic Diseases ◽

Steroid Hormone ◽

Protein Protein Interactions ◽

Hormone Biosynthesis ◽

Differentiation And Proliferation

miRNAs are endogenous noncoding single-stranded small RNAs of ~22 nucleotides in length that post-transcriptionally repress the expression of their various target genes. They contribute to the regulation of a variety of physiologic processes including embryonic development, differentiation and proliferation, apoptosis, metabolism, hemostasis and inflammation. In addition, aberrant miRNA expression is implicated in the pathogenesis of numerous diseases including cancer, hepatitis, cardiovascular diseases and metabolic diseases. Steroid hormones regulate virtually every aspect of metabolism, and acute and chronic steroid hormone biosynthesis is primarily regulated by tissue-specific trophic hormones involving transcriptional and translational events. In addition, it is becoming increasingly clear that steroidogenic pathways are also subject to post-transcriptional and post-translational regulations including processes such as phosphorylation/dephosphorylation, protein‒protein interactions and regulation by specific miRNAs, although the latter is in its infancy state. Here, we summarize the recent advances in miRNA-mediated regulation of steroidogenesis with emphasis on adrenal and gonadal steroidogenesis.

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MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target

Current Pharmaceutical Design ◽

10.2174/1381612826666201029095702 ◽

2020 ◽

Vol 26 ◽

Author(s):

Yini Ma ◽

Xiu Cao ◽

Guojuan Shi ◽

Tianlu Shi

Keyword(s):

Digestive System ◽

Target Genes ◽

Malignant Neoplasm ◽

Vital Role ◽

Diagnostic Biomarkers ◽

Cellular Processes ◽

Promising Therapeutic Target ◽

Direct Target ◽

Potential Strategy

: MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles for cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as valuable biomarkers for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.

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