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Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
In addition, cell cycle progression upon treatment with RA is dependent on the cyclin family of proteins, in particular Cyclin C expression. As a partner of cyclin-dependent kinase 3 (CDK3), Cyclin C controls cellular proliferation and, together with CDK8, represses gene transcription. Cyclin C gene is a direct target for RA in HEK293 human embryonal kidney cells, containing two RAR binding sites (88).
TP53 in cancer origin and treatment
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Elena A. Komarova, Peter M. Chumakov, Andrei V. Gudkov
G1 arrest. The TP53-dependent G1 arrest results mainly from transactivation of the WAF1 gene (wild-type TP53-activated factor) (el-Deiry et al., 1993), also known as CIP1 (Cdk-interacting protein 1) (Harper et al., 1993) or SDI1 (senescent cell-derived inhibitor) (Noda et al., 1994), that encodes the small protein p21, an inhibitor of cyclin-dependent kinases (Cdks). p21 interferes with cell-cycle progression and prevents S phase entry by blocking the activity of Cdks (Cdk2, Cdk3, Cdk4, and Cdk6). Cdks are catalytic partners of the cyclins, controlling cell-cycle progression (Dulic et al., 1994; el-Deiry et al., 1993). Although p21 is a TP53-responsive gene, it is a subject of complex transcriptional regulation that is, in part, TP53-independent (Macleod et al., 1995). Up-regulation of P21 often interferes with the induction of apoptosis (Gorospe et al., 1996; Polyak et al., 1996). Although p21 knockout cells have impaired G1 checkpoint control, inactivation of p21 does not result in any severe phenotype and does not match the consequences of tp53 knockout mice (Brugarolas et al., 1995; Deng et al., 1995; Komarova et al., 2000). Abrogation of the G1 checkpoint results in a higher proportion of cells arrested at other checkpoints and, in some cases, increases sensitivity to apoptosis (Gartel et al., 1996; Komarova et al., 2000; Wang et al., 1996b).
Regulation of Cell Functions
Published in Enrique Pimentel, Handbook of Growth Factors, 2017
In conclusion, control of the cell cycle is effected through the combined actions of proteins that are members of the cyclin and cdc2 families. Control of cell division at the G2 to M phase transition depends on the activation of a protein kinase composed of a catalytic subunit, cdc2, whose levels are not altered during the different phases of the cycle, and a regulatory subunit, cyclin B, whose levels oscillate in synchrony with the cell cycle. Phosphorylation/dephosphorylation of the cdc2 kinase by Wee-1 and other kinases at specific tyrosine and threonine residues contributes to the regulation of its enzymatic activity. While phosphorylation of the cdc2 protein on Thr-14 and Tyr-15 inhibits its kinase activity, dephosphorylation at the same residues results in cdc2 kinase activation, coincident with the initiation of mitosis. The cdc2-cyclin B protein kinase complex remains active until the end of mitosis, when cyclin B is degraded and cdc2 is released as an inactive monomer. A second type of control involving the cdk2 kinase and cyclin E operates in human cells for regulation of the G1 to S phase transition (Figure 1.3). Substrates for the cdk2 kinase include the RB tumor suppressor protein and the E2F transcription factor. The roles of other members of the cyclin and cdc2-related protein families in the regulation of the cell cycle remain to be elucidated, but multiple interactions between these proteins may be important for cell cycle control. Restimulation of growth factor-deprived cells to enter the cycle results in the accumulation of complexes between cyclin D and several cdk kinases (cdk2, cdk4, cdk5), and these complexes appear earlier in the G1 phase than do the cdk2-cyclin E complexes, which are expressed mainly before the G1/S phase transition. Proteins related to cdk2, including one called cdk3, may also participate in cell cycle control, but their precise roles are not understood at present.362 It is clear that, although in the last few years there have been important advances in our knowledge of the mechanisms that are directly involved in the control of the cell cycle in species ranging from yeast to man, further studies are required for a better characterization of the precise role of each type of control and for the mechanisms by which they are regulated by growth factors.
Cyclin-dependent kinase inhibitors for the treatment of lung cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Angel Qin, Haritha G. Reddy, Frank D. Weinberg, Gregory P. Kalemkerian
A number of cell-cycle independent CDKs are important transcriptional regulators. CDK7, CDK8, CDK 9 and CDK11 are all involved in the regulation of transcriptional and splicing machinery [11]. Since deregulation of transcription is one of the hallmarks of cancer, transcription-regulating CDKs are rational therapeutic targets. For example, CDK7 is a vital component of the general transcription factor, TFIIH, which phosphorylates RNA polymerase II, a critical enzyme driving transcriptional initiation and elongation and DNA repair. The functions of several CDKs remain largely unknown. CDK3 appears to be involved in cell cycle control, but mouse studies have shown that many strains have inherently inactivated CDK3 without a major phenotypic effect, indicating that CDK3 is not essential [38]. CDK5 has recently been demonstrated to be important in driving progression from G1 to S phase in medullary thyroid cancer [39].
Development of newly synthesised quinazolinone-based CDK2 inhibitors with potent efficacy against melanoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Eman R. Mohammed, Ghada F. Elmasry
Cyclin-dependent kinases (Cdks) are serine/threonine kinases. The mammalian cells contain 13 CDKs, among them CDK1, CDK2, CDK3, CDK4, and CDK6 which are involved in regulating the cell cycle checkpoints via initiation of proteinaceous substrates phosphorylation, using adenosine triphosphate (ATP)2,3. Abnormalities in the cell cycle regulation induce unrestricted cell growth, which is usually considered a hallmark of cancer4. Disruption of a deregulated cell cycle, as a result of overactivation of a CDK, has been accepted as a strategy for the treatment of proliferative diseases, especially cancer5.
Lappaol F regulates the cell cycle by activating CDKN1C/p57 in human colorectal cancer cells
Published in Pharmaceutical Biology, 2023
Rui-Yi Yang, Jia-Yi Tan, Zhe Liu, Xiao-Ling Shen, Ying-Jie Hu
The normal cell cycle sequentially goes through G1, S, G2, and M phases for cell proliferation. The transition between the cell cycle phases of eukaryotic cells is governed by the ordered activation of a set of cyclin–CDK complexes, and CDKNs inhibit the activities of these complexes at appropriate check points. Ultra-powerful ‘engines’ (such as cyclins and CDKs) and defective ‘brakes’ (such as CDKNs) lead to uncontrolled cell cycle and excessive cell proliferation (Lim and Kaldis 2013). Therefore, cell cycle dysregulation is a common process in the development of cancer (Peng et al. 2021). Known to date, CDKNs are divided into two distinct families, INK4 and CIP/KIP. Members of the INK4 family (CDKN2A/p16INK4a, CDKN2B/p15INK4b, CDKN2C/p18 INK4c, and CDKN2D/p19 INK4d) specifically inhibit the activities of CDK4 and CDK6, whereas CIP/KIP members (CDKN1A/p21CIP1, CDKN1B/p27KIP1, CDKN1C/p57KIP2, and CDKN3CIP2) control a broad spectrum of cyclin–CDK complexes. In this study, CDKN1C/p57 was the most significantly upregulated among all 127 LAF-induced DEPs. CDKN1C/p57, which is highly homologous to CDKN1B/p27, has also been identified as a tumor suppressor (Lee et al. 1995; Matsuoka et al. 1995). Low expression of CDKN1C/p57 has been observed in many types of tumors and is significantly correlated with poor prognosis and aggressive form of the disease (Pateras et al. 2009; Borriello et al. 2011; Lai et al. 2021). During colorectal carcinogenesis, CDKN1C/p57 downregulation is associated with the transition from adenoma to carcinoma and large size of the tumor (Noura et al. 2001; Li et al. 2003). The association between cancer and CDKN1C/p57 expression suggests that increase in CDKN1C/p57 levels may be advantageous for cancer therapy. Similar to CDKN1A/p21 and CDKN1B/p27, CDKN1C/p57 inhibits a series of cyclin–CDK complexes, including CCNE–CDK2, CCNA–CDK2, CCNE–CDK3, CCND1–CDK4, CCND2–CDK4, and to a lesser extent, CCNB–CDK1 and CCND2–CDK6 (Lee et al. 1995; Matsuoka et al. 1995; Reynaud et al. 2000). CCNA–CDK2 has previously been identified as an imperative kinase for DNA replication and S-phase progression (Fotedar et al. 1996; Morgan 2008). In addition, CCNA–CDK2 regulates the timing of CCNB–CDK1 activation during the late S/G2 phase and mediates the S phase exit and G2 phase transition of cells (Oakes et al. 2014). Downregulation of CCNA2 and CDK2 induces the cell cycle at S phase (Cheng et al. 2020). Consistent with the upregulation of CDKN1C/p57 by LAF, the expression of CCNA2, CDK2, CCNB1, and CDK1 was subsequently inhibited, leading to S-phase arrest in SW480 CRC cells.