Driver Mutations
John Melford in Pocket Guide to Cancer, 2017
We don’t have a full understanding of the complexities of p53 involvement in mediating cell fate. In normal unstressed cells, p53 attached to mdm2 is maintained at low steady-state levels by its continual breakdown, which restricts its impact on cell fate. In response to DNA damage, p53 is phosphorylated, which causes it to dissociate from mdm2. This reduces the rate at which it is broken down, leading to its accumulation. It is now able to bind to the promoter regions of genes and initiate their synthesis. First, p21 is synthesized, which arrests the cell cycle by inhibiting one or more kinases that drives it forward, as shown in Figure 11.4. Second, if p53 activation continues for a prolonged period of time, the synthesis of other proteins is initiated that induce apoptosis. This ensures cells with damaged DNA, that are not repaired within a given time frame, are killed.
Irradiation-induced damage and the DNA damage response
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
Cells contain a checkpoint at the transition between the G1 and S phases that plays an important normal role in the decision of the cell to initiate DNA replication for subsequent cell division. This checkpoint is thus sensitive to growth factors, nutrients and other conditions that favour proliferation. The transition from G1 to the S phase is controlled by the activation of the E2F transcription factor which is important for regulating many of the genes necessary to initiate DNA replication. E2F is kept inactive in G1 by binding to the retinoblastoma (Rb) protein. As cells normally move from G1 into S, the Rb protein becomes phosphorylated by cyclinD/CDK4 and cyclinE/CDK2. This phosphorylation causes release of Rb from E2F, allowing E2F to function as a transcription factor and initiate the S phase. As described previously, irradiation leads to an ATM-dependent stabilization and activation of p53. One of the genes that are upregulated by p53 is the CDKI p21 (CDKN1A). The p21 inhibits the G1 cyclin/CDK complexes, thereby preventing phosphorylation of Rb and entry into the S phase. As a result, cells that are irradiated while in the G1 phase will exhibit a delay prior to entry into the S phase that is dependent on both p53 and p21.
Oncogenesis and Metastasis
Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple in Basic Urological Sciences, 2021
Functions as a transcription factor:Regulates expression of cell cycle control genes.Transcriptionally activates p21 → p21 protein inhibits CDKs.Despite cyclins being present, CDKs cannot activate downstream pathways.Cell will not progress through G1/S checkpoint.Cell cycle is ‘stalled’ until genetic repair is completed.If DNA damage is irreparable, prolonged TP53 activation may trigger cell death.
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.
Bone marrow derived mesenchymal stem cells transplantation rescues premature ovarian insufficiency induced by chemotherapy
Published in Gynecological Endocrinology, 2018
Riqiang Bao, Ping Xu, Yishu Wang, Jing Wang, Li Xiao, Gang Li, Chunping Zhang
In fact, the growth of normal follicles is characterized by ovarian cell proliferation, especially granulosa cells. These ovarian cells work together to synthesize estrogen and regulate normal reproductive function [39]. Overapoptosis of ovarian cells induced by chemotherapy drugs caused a declined serum estrogen level. However, the recovery of estrogen level should be associated with the increase of ovarian cell proliferation. To date, almost all studies focused on the anti-apoptosis function and underneath mechanism of MSCs in POF treatment. Encouraging results from our study revealed that BM-MSCs increased the CyclinD2 expression and decreased p21 expression. CyclinD2 is critical in promoting cell cycle progress. CyclinD2 deficiency in ovarian granulosa cells influenced the proliferation and caused infertile of females [40]. p21, known as cyclin-dependent kinase inhibitor 1A (CDKN1A), exerts its function through binding to cyclins and cyclin-dependent kinases (CDKs) directly, which lead cell arrest at G1/S and G2/M transitions [41]. Cell cycle progression is precisely regulated by cyclins and several CDKs. Based on our results, we inferred that BM-MSCs transplantation regulated CyclinD2 and p21 expression and increased residual ovarian cell proliferation and restored ovarian function.
Functional variants of p21 gene alter susceptibility to meningioma
Published in British Journal of Biomedical Science, 2018
S Mashayekhi, Z Salehi, A Saberi, M Shakiba, F Mashayekhi, S Yousefzadeh-Chabok
Meningioma is the most common brain tumour, arising from arachnoid cells of the meninges. It accounts for almost 37% of all primary brain tumours. According to the World Health Organization (WHO), meningioma is categorized into three grades. The recurrence rate of grade I, II and III at 5 years after complete resection is approximately 10, 50 and 80%, respectively [1]. The complex aetiology of meningioma involves a combination of environmental factors and genetic impairments. Head trauma, occupational exposure, mobile phones, female sex hormones and smoking may contribute to meningioma [2]. p21 (also named CDKN1A or WAF1/Cip1) is a central mediator of the p53 checkpoint control on chromosome 6p21.2. p21 protein has multiple functions, such as control of cell motility, regulation of apoptosis, transcriptional activity, inhibition of cell proliferation and action as a tumour suppressor [3].
Related Knowledge Centers
- Chromosome 6
- Cyclin
- P53
- Cell Cycle
- Cyclin-Dependent Kinase Inhibitor Protein
- Cyclin-Dependent Kinase Complex
- Cyclin-Dependent Kinase 2
- Gene
- Cyclin-Dependent Kinase 1
- Cyclin-Dependent Kinase 4