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Adenoviral Vectors for Gene Therapy of Inherited and Acquired Disorders of the Lung
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
David T. Curiel, Robert I. Garver
Recently, the pl6INK4 gene has been shown in one study to mitigate the malignant phenotype in human lung cancer cell lines not expressing the normal gene product (81). In this study by Jin et al., an adenoviral vector containing the pl6INK4 coding sequence administered in vitro to several human NSCLC cell lines resulted in markedly diminished in vitro growth. One of the cell lines was found to have moderately reduced in vivo growth when the cells were engrafted into immunosuppressed mice following the adenovirus treatment. These results suggest that the pl6INK4 gene is a candidate tumor suppressor gene that could be administered in a therapeutic context to NSCLC, although the data are more preliminary than those obtained with p53.
The Cell and Cell Division
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
In part, this process is controlled by the synthesis and degradation of the cyclins, but it is also affected by phosphorylation of the CDK on two sites (Fig. 22), which is controlled by two phosphatases known as Wee1 and MO15. Removal of one of the phosphate residues by means of another phosphatase—Cdc25— is then needed for activation of MPF. It is thought that the MPF autocatalytically activates itself, resulting in a steady rise in MPF levels during the cell cycle until the critical point when an explosive increase in activity takes place and drives the cell irretrievably into the M phase. Cdc2 is associated with the G1/S, and the G2/M transitions and cdc4 and cdc6 are associated with start, but are bound to different cyclins (cyclin B at mitosis and cyclin E and A at start at G1/S). The Kip/cip family of cyclin-dependent kinases, which include p21, p27 and p57, are capable of binding to and inhibiting most cyclin/CDK complexes. The expression of these CDK inhibitors is often dependent on upstream events that are activated by physiological signals, such as DNA damage, serum deprivation, or contact inhibition. In contrast, the INK4 family of CDK inhibitors, including p15, p16, p18, and p19, bind to and inactivate D-type cyclins.
Genetics of liver cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
A.-M. Hui, L. Sun, M. Makuuchi
The CDK inhibitor INK4 is also considered to be a tumor suppressor. However, in contrast to classical tumor suppressor genes, INK4 can be inactivated by a variety of genetic or epigenetic events, including homozygous deletion (Carins et al., 1995; Nobori et al., 1994), mutation (Caldas et al., 1994; Hussussian et al., 1994), hypermethylation of the 5′ CpG island in the promotor region (Herman et al., 1995; Merlo et al., 1995) and post-transcriptional regulation (Hui et al., 1996a; Kovareia et al., 1997).
Protective effect of Pulsatilla saponin A on acute myocardial infarction via miR-24-3p/p16
Published in Toxicology Mechanisms and Methods, 2022
Feng Dong, Yanhua Pu, Yanfei Lv, Xiujuan Liu, Yimin Cao
The p16 (MTS-1, INK4a, p16INK4, or CDKN2A) gene is a member of the INK4 family and has biological properties of inhibition of cell growth (Serra and Chetty 2018). It has been proved that p16 may be a sensitive gene of coronary heart disease (Tian et al. 2013), and its expression may be associated with the susceptibility of coronary heart disease. For example, resveratrol attenuated myocardial infarction area, fibrosis, and apoptosis by restraining the levels of senescence markers (p53, p16, and p19), inflammasome markers, and nuclear translocation of NF-B (Feng et al. 2020). The deficiency of Cnpy2 can lead to an increase in p16 expression which damaged cardiac function and tissue repair (Yin et al. 2019). A previous study demonstrated miR-24 was found to be the regulator of p16INK4a-associated senescent phenotypes during osteoarthritis progression (Philipot et al. 2014). MiR-24 facilitates the proliferation of primary keratinocyte and cancer cell lines through directly targeting p27Kip1 and p16Ink4a (Giglio et al. 2013). But the targeting mechanism of miR-24-3p on p16 in AMI needs further study.
An evaluation of palbociclib as a breast cancer treatment option: a current update
Published in Expert Opinion on Pharmacotherapy, 2021
Gregory T. Gallanis, Ramon I. Pericas, Anna T. Riegel, Paula R. Pohlmann
During the early G1 phase of the cell cycle, mitogenic signaling converges upon the induction of expression of D-type cyclins, which assemble with CDK4 or CDK6 to phosphorylate retinoblastoma protein (RB) and its related family members [2–9]. The role of RB is to repress activity of the E2F family of transcription factors that would otherwise drive transcription of cell cycle-progression genes [10]. Active cyclin D-CDK4/6 complexes phosphorylate and inactivate RB, which permits E2F-driven transcription of cyclin E and forms a feed-forward loop as cyclin E joins with CDK2 to further phosphorylate and inactivate RB [5]. Subsequently, remaining inhibitory pressure from RB is mitigated and the full suite of E2F-regulated genes is transcribed to produce the proteins necessary to carry out DNA synthesis and progress to later stages of the cell cycle [11,12]. Cyclin-CDK complexes are regulated by endogenous inhibitory proteins and post-translational modification [13]. INK4 family proteins such as the prototypical p16INK4A directly bind CDK4 to inhibit cyclin D-CDK4 activity [14]. Cyclin D-CDK4 is also regulated by cyclin H-CDK7, which critically activates the complex by phosphorylation of CDK4 at the T172 residue [15]. p21CIP1 and p27KIP1 regulate cyclin E-CDK2 complexes, and sequestration of these inhibitors by cyclin D-CDK4/6 enables further phosphorylation of RB and RB-like family members at the G1/S checkpoint [14] (Figure 1).
Emerging therapeutic targets for nasopharyngeal carcinoma: opportunities and challenges
Published in Expert Opinion on Therapeutic Targets, 2020
Valentin Baloche, François-Régis Ferrand, Anna Makowska, Caroline Even, Udo Kontny, Pierre Busson
Regarding Rb and TP53, it is useful to remind that the active Rb protein maintains a physiological barrier at the entry of the cell cycle (G0/G1 transition) whereas TP53 has the power to induce cell cycle arrest or apoptosis, especially in a context of Rb deregulation. Therefore, structural or functional inactivation of both proteins is a common feature of most human malignancies. Inactivating mutations of Rb rarely occur in NPCs. However, in most cases, Rb is functionally inactivated by its phosphorylation resulting from inappropriate activity of the cyclin-dependent kinases CDK4 and CDK6. Indeed, in most NPCs, CDKN2A silencing and/or CCND1 overexpression result in the deregulation of CDK4/6. The CDKN2A gene maps to chromosome 9p21. By alternate reading of the same frame, it encodes 2 proteins named INK4 (p16) and ARF (p14). INK4 is a negative regulator of the CDK4/6-cyclin-D1 complex whereas ARF is an inhibitor of MDM2 (an E3-ubiquitin ligase involved in the degradation of TP53). CDKN2A is the most frequently altered tumor suppressor gene in NPCs (about 80% of the cases). It is silenced through loss of the 2 alleles or loss of one allele and methylation of the promoter of the remaining allele [33,34]. Like in other Head and Neck carcinomas, the CCND1 gene is frequently amplified resulting in overexpression of cyclin D1 (15% of NPC cases) [35].