scholarly journals Gli Proteins: Regulation in Development and Cancer

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 147 ◽  
Author(s):  
Paweł Niewiadomski ◽  
Sylwia M. Niedziółka ◽  
Łukasz Markiewicz ◽  
Tomasz Uśpieński ◽  
Brygida Baran ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Birth Defects ◽  
Tissue Regeneration ◽  
Posttranslational Modifications ◽  
Hedgehog Signaling ◽  
Intracellular Transport ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Gli Proteins ◽  
Fine Tune

Gli proteins are transcriptional effectors of the Hedgehog signaling pathway. They play key roles in the development of many organs and tissues, and are deregulated in birth defects and cancer. We review the molecular mechanisms of Gli protein regulation in mammals, with special emphasis on posttranslational modifications and intracellular transport. We also discuss how Gli proteins interact with co-activators and co-repressors to fine-tune the expression of Hedgehog target genes. Finally, we provide an overview of the regulation of developmental processes and tissue regeneration by Gli proteins and discuss how these proteins are involved in cancer progression, both through canonical regulation via the Hedgehog pathway and through cross-talk with other signaling pathways.

scholarly journals The role of m6A modification in the biological functions and diseases

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiulin Jiang ◽  
Baiyang Liu ◽  
Zhi Nie ◽  
Lincan Duan ◽  
Qiuxia Xiong ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Modification ◽  
Biological Functions ◽  
Rna Methylation ◽  
Downstream Target ◽  
Different Types ◽  
M6a Rna Methylation

AbstractN6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as “readers”. Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.

Calcineurin regulates the stability and activity of estrogen receptor α

2021 ◽  
Vol 118 (44) ◽  
pp. e2114258118
Author(s):  
Takahiro Masaki ◽  
Makoto Habara ◽  
Yuki Sato ◽  
Takahiro Goshima ◽  
Keisuke Maeda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
The Stability ◽  
Positive Breast Cancer

Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A–α gene (PPP3CA) was associated with poor prognosis in ER-α–positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α–positive breast cancer.

The Use of Chemical Compounds to Identify the Regulatory Mechanisms of Vertebrate Circadian Clocks

2020 ◽  
Vol 21 (5) ◽  
pp. 425-432
Author(s):  
Yoshimi Okamoto-Uchida ◽  
Akari Nishimura ◽  
Junko Izawa ◽  
Atsuhiko Hattori ◽  
Nobuo Suzuki ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Chemical Compounds ◽  
Stability Control ◽  
Circadian Clocks ◽  
Light Signaling ◽  
Negative Feedback Loops ◽  
Exact Timing

Circadian clocks are intrinsic, time-tracking processes that confer a survival advantage on an organism. Under natural conditions, they follow approximately a 24-h day, modulated by environmental time cues, such as light, to maximize an organism’s physiological efficiency. The exact timing of this rhythm is established by cell-autonomous oscillators called cellular clocks, which are controlled by transcription–translation negative feedback loops. Studies of cell-based systems and wholeanimal models have utilized a pharmacological approach in which chemical compounds are used to identify molecular mechanisms capable of establishing and maintaining cellular clocks, such as posttranslational modifications of cellular clock regulators, chromatin remodeling of cellular clock target genes’ promoters, and stability control of cellular clock components. In addition, studies with chemical compounds have contributed to the characterization of light-signaling pathways and their impact on the cellular clock. Here, the use of chemical compounds to study the molecular, cellular, and behavioral aspects of the vertebrate circadian clock system is described.

scholarly journals Molecular Mechanisms of Colon Cancer Progression and Metastasis: Recent Insights and Advancements

2020 ◽  
Vol 22 (1) ◽  
pp. 130
Author(s):  
Ahmed Malki ◽  
Rasha Abu ElRuz ◽  
Ishita Gupta ◽  
Asma Allouch ◽  
Semir Vranic ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Cellular Signaling ◽  
Clinical Care ◽  
Underlying Mechanism ◽  
Cellular Mechanisms ◽  
Colon Cancer Progression ◽  
Crc Management

Colorectal cancer (CRC), the third most common type of cancer, is the second leading cause of cancer-related mortality rates worldwide. Although modern research was able to shed light on the pathogenesis of CRC and provide enhanced screening strategies, the prevalence of CRC is still on the rise. Studies showed several cellular signaling pathways dysregulated in CRC, leading to the onset of malignant phenotypes. Therefore, analyzing signaling pathways involved in CRC metastasis is necessary to elucidate the underlying mechanism of CRC progression and pharmacotherapy. This review focused on target genes as well as various cellular signaling pathways including Wnt/β-catenin, p53, TGF-β/SMAD, NF-κB, Notch, VEGF, and JAKs/STAT3, which are associated with CRC progression and metastasis. Additionally, alternations in methylation patterns in relation with signaling pathways involved in regulating various cellular mechanisms such as cell cycle, transcription, apoptosis, and angiogenesis as well as invasion and metastasis were also reviewed. To date, understanding the genomic and epigenomic instability has identified candidate biomarkers that are validated for routine clinical use in CRC management. Nevertheless, better understanding of the onset and progression of CRC can aid in the development of early detection molecular markers and risk stratification methods to improve the clinical care of CRC patients.

scholarly journals GLI transcriptional repression regulates tissue-specific enhancer activity in response to Hedgehog signaling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Rachel K Lex ◽  
Zhicheng Ji ◽  
Kristin N Falkenstein ◽  
Weiqiang Zhou ◽  
Joanna L Henry ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Limb Bud ◽  
Enhancer Activity ◽  
Tissue Specific ◽  
Major Mechanism ◽  
Gli Proteins ◽  
Repression Complex ◽  
Mouse Limb

Transcriptional repression needs to be rapidly reversible during embryonic development. This extends to the Hedgehog pathway, which primarily serves to counter GLI repression by processing GLI proteins into transcriptional activators. In investigating the mechanisms underlying GLI repression, we find that a subset of GLI binding regions, termed HH-responsive enhancers, specifically loses acetylation in the absence of HH signaling. These regions are highly enriched around HH target genes and primarily drive HH-specific transcriptional activity in the mouse limb bud. They also retain H3K27ac enrichment in limb buds devoid of GLI activator and repressor, indicating that their activity is primarily regulated by GLI repression. Furthermore, the Polycomb repression complex is not active at most of these regions, suggesting it is not a major mechanism of GLI repression. We propose a model for tissue-specific enhancer activity in which an HDAC-associated GLI repression complex regulates target genes by altering the acetylation status at enhancers.

scholarly journals CircPTPRA blocks the recognition of RNA N6-methyladenosine through interacting with IGF2BP1 to suppress bladder cancer progression

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Fei Xie ◽  
Chao Huang ◽  
Feng Liu ◽  
Hui Zhang ◽  
Xingyuan Xiao ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Clinical Role ◽  
Rna Immunoprecipitation

Abstract Background Circular RNAs (circRNAs) have been found to have significant impacts on bladder cancer (BC) progression through various mechanisms. In this study, we aimed to identify novel circRNAs that regulate the function of IGF2BP1, a key m6A reader, and explore the regulatory mechanisms and clinical significances in BC. Methods Firstly, the clinical role of IGF2BP1 in BC was studied. Then, RNA immunoprecipitation sequencing (RIP-seq) analysis was performed to identify the circRNAs interacted with IGF2BP1 in BC cells. The overall biological roles of IGF2BP1 and the candidate circPTPRA were investigated in both BC cell lines and animal xenograft studies. Subsequently, we evaluated the regulation effects of circPTPRA on IGF2BP1 and screened out its target genes through RNA sequencing. Finally, we explored the underlying molecular mechanisms that circPTPRA might act as a blocker in recognition of m6A. Results We demonstrated that IGF2BP1 was predominantly binded with circPTPRA in the cytoplasm in BC cells. Ectopic expression of circPTPRA abolished the promotion of cell proliferation, migration and invasion of BC cells induced by IGF2BP1. Importantly, circPTPRA downregulated IGF2BP1-regulation of MYC and FSCN1 expression via interacting with IGF2BP1. Moreover, the recognition of m6A-modified RNAs mediated by IGF2BP1 was partly disturbed by circPTPRA through its interaction with KH domains of IGF2BP1. Conclusions This study identifies exonic circular circPTPRA as a new tumor suppressor that inhibits cancer progression through endogenous blocking the recognition of IGF2BP1 to m6A-modified RNAs, indicating that circPTPRA may serve as an exploitable therapeutic target for patients with BC.

scholarly journals Defining the Role of GLI/Hedgehog Signaling in Chemoresistance: Implications in Therapeutic Approaches

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4746
Author(s):  
Jian Yi Chai ◽  
Vaisnevee Sugumar ◽  
Ahmed F. Alshanon ◽  
Won Fen Wong ◽  
Shin Yee Fung ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cancer Progression ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Cancer Treatments ◽  
Mesenchymal Transition ◽  
Hh Signaling

Insight into cancer signaling pathways is vital in the development of new cancer treatments to improve treatment efficacy. A relatively new but essential developmental signaling pathway, namely Hedgehog (Hh), has recently emerged as a major mediator of cancer progression and chemoresistance. The evolutionary conserved Hh signaling pathway requires an in-depth understanding of the paradigm of Hh signaling transduction, which is fundamental to provide the necessary means for the design of novel tools for treating cancer related to aberrant Hh signaling. This review will focus substantially on the canonical Hh signaling and the treatment strategies employed in different studies, with special emphasis on the molecular mechanisms and combination treatment in regard to Hh inhibitors and chemotherapeutics. We discuss our views based on Hh signaling’s role in regulating DNA repair machinery, autophagy, tumor microenvironment, drug inactivation, transporters, epithelial-to-mesenchymal transition, and cancer stem cells to promote chemoresistance. The understanding of this Achilles’ Heel in cancer may improve the therapeutic outcome for cancer therapy.

scholarly journals The Dual Role of MicroRNAs in Colorectal Cancer Progression

2018 ◽  
Vol 19 (9) ◽  
pp. 2791 ◽  
Author(s):  
Lei Ding ◽  
Zhenwei Lan ◽  
Xianhui Xiong ◽  
Hongshun Ao ◽  
Yingting Feng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Profiles ◽  
Dual Role ◽  
Aberrant Expression ◽  
Cellular Environment ◽  
Incidence And Mortality ◽  
Context Specific

Colorectal cancer (CRC) is responsible for one of the major cancer incidence and mortality worldwide. It is well known that MicroRNAs (miRNAs) play vital roles in maintaining the cell development and other physiological processes, as well as, the aberrant expression of numerous miRNAs involved in CRC progression. MiRNAs are a class of small, endogenous, non-coding, single-stranded RNAs that bind to the 3’-untranslated region (3′-UTR) complementary sequences of their target mRNA, resulting in mRNA degradation or inhibition of its translation as a post-transcriptional regulators. Moreover, miRNAs also can target the long non-coding RNA (lncRNA) to regulate the expression of its target genes involved in proliferation and metastasis of CRC. The functions of these dysregulated miRNAs appear to be context specific, with evidence of having a dual role in both oncogenes and tumor suppression depending on the cellular environment in which they are expressed. Therefore, the unique expression profiles of miRNAs relate to the diagnosis, prognosis, and therapeutic outcome in CRC. In this review, we focused on several oncogenic and tumor-suppressive miRNAs specific to CRC, and assess their functions to uncover the molecular mechanisms of tumor initiation and progression in CRC. These data promised that miRNAs can be used as early detection biomarkers and potential therapeutic target in CRC patients.

scholarly journals GLI transcriptional repression regulates tissue-specific enhancer activity in response to Hedgehog signaling

2019 ◽  
Author(s):  
Rachel K. Lex ◽  
Zhicheng Ji ◽  
Kristin N. Falkenstein ◽  
Weiqiang Zhou ◽  
Joanna L. Henry ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Hedgehog Signaling ◽  
Target Gene ◽  
Target Genes ◽  
Enhancer Activity ◽  
Tissue Specific ◽  
Major Mechanism ◽  
Gli Proteins ◽  
Polycomb Repression ◽  
Repression Complex

ABSTRACTTranscriptional repression needs to be rapidly reversible during embryonic development. This extends to the Hedgehog pathway, which primarily serves to counter GLI repression by processing GLI proteins into transcriptional activators. In investigating the mechanisms underlying GLI repression, we find that a subset of these regions, termed HH-responsive enhancers, specifically loses acetylation in the absence of HH signaling. These regions are highly enriched around HH target genes and primarily drive HH-specific limb activity. They also retain H3K27ac enrichment in limb buds devoid of GLI activator and repressor, indicating that their activity is primarily regulated by GLI repression. The Polycomb repression complex is not active at most of these regions, suggesting it is not a major mechanism of GLI repression. We propose a model for tissue-specific enhancer activity in which an HDAC-associated GLI repression complex regulates target gene expression by altering the acetylation status at enhancers.

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