Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Transcription factors are proteins that control the DNA transcriptional process by selectively binding to a target sequence in the promoter region of the relevant gene to stimulate or inhibit transcription. They work by modifying the activity of RNA Polymerase II (Pol II) to ensure that transcription occurs (or not) at the appropriate time and place in the genome. Cancer therapies based on inhibiting the transcription of oncogenes such as C-Myc, HIF-1, NFκB, and STAT-3 have been envisaged. A number of small molecules inhibitors have been reported such as alvocidib, echinomycin, PBD molecules (e.g., TSG-1301), and the hairpin polyamides that can bind to duplex DNA in a sequence-selective manner and inhibit transcription. Some of these molecules are described in Section 5.7.1.1.1, although none have reached the approval stage.
Cellular and Molecular Basis of Human Biology
Lawrence S. Chan, William C. Tang in Engineering-Medicine, 2019
The human genome is consisted of 20,000 different genes and nucleic acids composed of 3 billion base pairs (Green et al. 2015). For the basic components of nucleic acid, the nucleotides, there are only 4 distinct nitrogenous bases: adenosine (short for A), thymine (T), guanine (G), and cytosine (C) and each nucleotide also contains a phosphate group and a sugar deoxyribose. One interesting and important fact is that virtually all differentiated cells have the identical and entire genome. Yet some proteins are produced by certain cell types and not by other cell types. The key factor is transcriptional factors, which function to bind to promoter region of DNA in initiating mRNA transcription. The binding of transcriptional factors enables the binding of RNA polymerase to DNA for the transcription. Activation and inactivation of certain transcriptional factors during human development determine the ability and inability to express certain proteins, and by extension their phenotype expressions, respectively (Hillis et al. 2014). Another interesting and also essential fact is that reactivation of cell-specific transcriptional factors could change a cell’s phenotype. For example, transgenic introduction of neuron-specific transcription factors into fibroblasts turn these connective tissue protein-producing cells into functional neurons with characteristic neuronal synapses (Hillis et al. 2014).
Genetics of Endocrine Disorders and Diabetes Mellitus
George H. Gass, Harold M. Kaplan in Handbook of Endocrinology, 2020
The promoter region of the GH gene regulates somatotroph-specific expression of GH. Transcription factors interact with the promoter to control gene expression. There are four main categories of transcription factors that interact with the GH gene promoter:10 Pit-1 or GHF-1; CTF/NF-1, USF/MCTF, SP1; inhibitory factors; and GCR, TR, RAR, RXR. Pit-1 (GHF-1) is a POU domain transcription factor expressed only in pituitary somatotrophs, lactotrophs, and thyrotrophs. The POU domain is a novel DNA-binding motif which appears to exert critical developmental actions. It is absolutely necessary for GH gene transcription in vivo.11 Much has been elucidated regarding expression of this factor, and it will be discussed in greater detail. The transcription factors CTF/NF-1, USF/MCTF, and SP1 are ubiquitous sequence-specific factors, and they are required for high-level activity of the GH promoter in pituitary cells. They do not activate the GH gene in nonpituitary cells.10,12 Inhibitory factors include inhibitory proteins that bind to silencer elements, such as silencer l.13 The inhibitory elements do not overlap with the stimulatory elements, so the mechanism does not appear to involve hindering access to positive regulators. The silencer proteins appear to attenuate GH gene expression.10 GCR, TR, RAR, and RXR are hormone-activated nuclear receptors. Their function in the context of the GH promoter is thought to involve opening of the GH chromatin structure to allow access for GHF-1 and other factors.10
Down-regulation of KLF9 ameliorates LPS-caused acute lung injury and inflammation in mice via reducing GSDMD expression
Published in Autoimmunity, 2022
Renliang Qu, Jingjing Liu, Lili Feng, Lianbing Li, Junwei Liu, Fengnan Sun, Lin Sun
Transcription factor is a type of nucleus protein, which can regulate the target genes through binding to DNA. They are recognised as the hub of various signalling pathways and play great therapeutic capabilities in multiple inflammatory diseases [42,43]. KLF9 has been reported as transcription factor of several genes. For example, KLF9 transcriptionally modulates 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), and participates in the metastasis of cutaneous squamous cell carcinoma [43]. KLF9 has also been proven to transcriptionally inhibit matrix metalloproteinase 28 (MMP28) expression in gastric cancer [44]. To explain the underlying mechanism of KLF9 in ALI, we accessed to JASPAR database and predicted the binding between KLF9 and the GSDMD promoter. GSDMD is a member of gasdermins, consisting of two conserved domains [45]. It can be cleaved N-terminal and C-terminal domains and extensively explored in pyroptosis [46]. Kovacs et al. have verified that cleaved N-terminal of GSDMD can form the memberane pores via cooperating with cell plasma membrane. This membrane pore could further contribute to the release of inflammatory cytokines [21]. Our results manifested that KLF9 knockdown induced a decreased expression of GSDMD in both in-vivo and in-vitro models. As expected, the levels of inflammatory factors were all reduced.
ANLN, Regulated by SP2, Promotes Colorectal Carcinoma Cell Proliferation via PI3K/AKT and MAPK Signaling Pathway
Published in Journal of Investigative Surgery, 2022
Yanwei Liu, Pengwei Cao, Feng Cao, Song Wang, Yan He, Yanyan Xu, Yong Wang
Transcription factors are gene regulators that recognize specific DNA sequences, bind chromatin, and form a complex that transcriptionally regulates the expression of genes [15]. We used bioinformatics tools based on JASPAR to predict the potential transcription factors that may regulate ANLN, and SP2 was strongly suggested as a regulator of ANLN according to the putative score. SP2 is a multifunctional transcription factor and cancer promoter in multiple tumors [13,14]. Our study results are consistent with these reports. SP2 depletion by targeted siRNA led to reduced levels of ANLN mRNA, which implied that ANLN-mediated control of CRC cell progression may be transcriptionally regulated by SP2. However, other external factors may be involved in ANLN regulation, such as the tumor microenvironment, and these potential regulatory elements require further investigation.
Effects of platelet-rich plasma on the pancreatic islet survival and function, islet transplantation outcome and pancreatic pdx1 and insulin gene expression in streptozotocin-induced diabetic rats
Published in Growth Factors, 2020
Marzieh Nemati, Narges Karbalaei, Pooneh Mokarram, Farzaneh Dehghani
Transcription factors have important roles in gene expression regulation. Pancreas/duodenum homeobox protein 1 (pdx1) that is known as insulin promoter factor 1 is one of the most transcription factors that play a critical role in pancreatic development, activation of insulin gene transcription, and regulation of adult islet beta cells function and insulin secretion (Huang and Tsai 2000; Laybutt et al. 2007). It has been shown that reduction of pdx1 gene expression in mature islet beta cells reduces the gene expression of insulin and other factors that are essential for GSIS and induces glucose intolerance (Servitja and Ferrer 2004; Laybutt et al. 2007; Zarin et al. 2019). There is considerable evidence on the positive effects of some growth factors in normalization of β-cell mass, improvement of impaired insulin secretion, and amelioration of hyperglycemia by up-regulation of transcription factors expression including pdx1 involved in pancreas development and regulation of insulin expression and secretion (Edlund 2002; Yu et al. 2012; Alvarez-Perez, Rosa, et al. 2014).
Related Knowledge Centers
- Cell Division
- DNA
- DNA Sequencing
- Gene Expression
- Molecular Biology
- Protein
- Messenger Rna
- Transcription
- Genetics
- Cell