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PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alicja M. Gruszkaa, Myriam Alcalay
An important example of a gene upregulated by PML/RARa expression is p21, as described by Viale et al. [56]. Haematopoietic cells are subjected to DNA damage upon PML/RARa expression that, if too extensive, could potentially become incompatible with the survival of the cell. Hence, the oncogene induces expression of p21, and therefore, a checkpoint, which leads to reversible cell-cycle arrest allowing for DNA repair. In this way, excessive DNA damage, incompatible with survival, and stem cell exhaustion are prevented.
Mechanism of Action of Isotretinoin
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
Isotretinoin treatment of SEB-1 sebocytes induced p21 (cyclin-dependent kinase inhibitor 1A [CDKN1A]) resulting in p21-dependent cell cycle arrest (4). p21 is the prototype of p53 target genes (78). In isotretinoin-treated SEB-1 sebocytes, upregulation of p21 led to cell cycle arrest (4). p21 prevents phosphorylation of the retinoblastoma (Rb) protein maintaining E2F-regulated genes in a repressed state, which leads to downregulation of SREBP1c and its downstream target stearoyl-CoA desaturase 1 (SCD), resulting in a decrease in mono-unsaturation of membrane phospholipids, decreased phosphatidylinositol-(4,5)-diphosphate (PIP2) and (phosphatidylinositol-(3,4,5)-triphosphate (PIP3) levels, and ultimately decreased phosphorylation and activation of AKT (79). Chronic activation of p53 in mice results in a loss of sebaceous glands (80). B-lymphocyte-induced nuclear maturation protein 1 (BLIMP1), a recently identified marker of differentiated sebocytes (81), binds to the TP53 promoter and represses p53 transcription (82), whereas epidermal-specific deletion of BLIMP1 resulted in sebaceous gland enlargement (81).
Regulators of Signal Transduction: Families of GTP-Binding Proteins
Published in Robert I. Glazer, Developments in Cancer Chemotherapy, 2019
In contrast to the trimeric G-protein cycle, the components referred to as activator and effector of p21 have not yet been identified. Furthermore, the biological activity measured with ras proteins is the induction of DNA synthesis over many hours. Experimental support for the model will require identification of the other components in the p21 pathway. Two approaches to identifying these components are described in a later section.
Nonlinearities in the cellular response to ionizing radiation and the role of p53 therein
Published in International Journal of Radiation Biology, 2021
David Murray, Razmik Mirzayans
Another p53-regulated gene, CDKN1A, encodes the p21WAF1 (henceforth, p21) protein which plays multiple roles in the DDR, such as in the activation of transient cell cycle checkpoints and of the senescence-like protracted growth arrest seen in many cell types (Crescenzi et al. 2008; Mirzayans et al. 2013; Murray et al. 2018) as well as promoting DNA repair (Dutto et al. 2015). p21 also inhibits apoptosis via a number of mechanisms, including downregulation/inhibition of pro-apoptotic genes/proteins and upregulation of anti-apoptotic genes (reviewed in Murray et al. 2018). It also mediates the ability of p53 to repress some genes (Lohr et al. 2003). Examples of genes that are negatively regulated by p53 are those encoding the anti-apoptotic proteins Bcl-2, MCL-1 (induced myeloid leukemia cell differentiation protein) and survivin.
In vitro study of the effects of DC electric fields on cell activities and gene expression in human choriocarcinoma cells
Published in Electromagnetic Biology and Medicine, 2021
Jinxin Chen, Linbo Guan, Ping Fan, Xinghui Liu, Rui Liu, Yu Liu, Huai Bai
Cyclin-dependent kinase inhibitor 1A (CDKN1A), also known as P21, is a member of the cyclin-dependent kinase inhibitor (CDKI) family. P21 is a negative regulator of cell cycle. P21 gene expression leads to enhanced cell cycle arrest and promotes DNA damage repair. Studies have shown that P21 blocks cells in the G2 phase (Gire and Dulic 2015). Previous studies have reported that EFs inhibit human lens vascular endothelial cell and epithelial cell proliferation (Wang et al. 2005, 2003), which are likely to be mediated through a cell cycle control mechanism. In human lens epithelial cells, EF stimulation decreases the entry of the cells into S phase from G1 phase (Wang et al. 2005). In contrast, we found that EF stimulation reduced the proportion of choriocarcinoma cells in the S phase, and most cells were blocked in the G2/M phase.
Obacunone reduces inflammatory signalling and tumour occurrence in mice with chronic inflammation-induced colorectal cancer
Published in Pharmaceutical Biology, 2020
Xiaoping Luo, Zhilun Yu, Bei Yue, Junyu Ren, Jing Zhang, Sridhar Mani, Zhengtao Wang, Wei Dou
The cell cycle is precisely controlled by specific proteins, including P21, cyclin A2, and cyclin E1. P21, a tumour suppressor gene, is involved in the regulation of cell proliferation by inhibiting the cyclin-dependent kinase (CDK) complex (Karimian et al. 2016). Cyclin A plays a role in the rate-limiting step for entry into mitosis and its overexpression accelerates the G1 to S transition causing DNA replication (Furuno et al. 1999). Accumulation of cyclin E at the transitional period of G1-S accelerates cells entry into the S phase (Lundberg and Weinberg 1998; Ewen 2000). We, therefore, performed immunoblot analysis of the protein levels of P21, cyclin A2, and cyclin E1 in Caco2 cells. Our results showed a significant increase in the P21 protein level after obacunone treatment (Figure 8(C)). Conversely, we observed a markedly decrease in cyclin A2 and cyclin E1 protein levels in Caco2 cells. Similarly, obacunone exerted prominently suppressive effects on mRNA levels of cell proliferation-related genes (CCNA2, CCND2, CCND3, CCNE1, CCNE2, CDK2, and P21; Figure 8(D)).