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2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) and Related Environmental Antiestrogens:Characterization and Mechanism of Action
Published in Rajesh K. Naz, Endocrine Disruptors, 2004
Recent studies in this laboratory have also focused on ER-AhR crosstalk associated with cell cycle enzymes. Several studies have reported that E2 decreases cells in G0/G1 and increases cells in S phase,147–150 and the pure antiestrogen ICI 182,780 inhibits many of these estrogenic responses. The specific cell cycle enzymes in MCF-7 cells, which are modulated by E2, show some variability between studies; however, cyclin-dependent kinase 2 (cdk2) and cdk4-associated activities are increased, and retinoblastoma (RB) protein phosphorylation, E2F1 protein, cyclin D1 mRNA, and protein levels are elevated. Results of recent studies in this laboratory showed that in addition to these responses, E2 also affected the cdk-activating kinase (CAK) that contains cyclin H/cdk7 proteins and plays an important role in phosphorylation (and activation) of both cdk2 and cdk4 at threonine-160 and threonine-170, respectively.151Although E2 did not affect levels of cyclin H protein, cdk7 levels were increased 2.1-fold 24 hours after treatment. Activation of cdk2/cdk4 is also dependent on cdc25 phosphatase-mediated hydrolysis of tyrosine 15, and in MCF-7 cells treated with E2 there was a significant increase (> twofold) in cdc 25 protein. Thus, treatment with cells with E2 activates multiple cell cycle proteins and related activity and thereby offers multiple targets for the indirect antiestrogenic activity of TCDD. Like ICI 182,780, TCDD inhibits cells from E2-induced progression into S phase and, in MCF-7 cells cotreated with E2 plus TCDD, there was selective inhibition of hormone-induced effects on cell cycle enzymes. For example, TCDD significantly inhibited the following E2-induced responses in MCF-7 cells: E2F1 protein, cyclin D protein and mRNA levels, phosphorylation of RB, and inhibition of cdk2-, cdk4, and cdk-7 associated kinase activities. Interestingly, TCDD alone had minimal effects on most cell cycle enzymes; however, in cells cotreated with E2 plus TCDD, there was a significant increase in p21 levels, and this response may contribute to decreased cdk2- and cdk4-associated activities. Ongoing studies in this laboratory are focused on delineating the molecular mechanisms of AhR crosstalk with hormone-regulated cell cycle enzymes in both in vitro and in vivo models.
A patent review of cyclin-dependent kinase 7 (CDK7) inhibitors (2018-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Markéta Kovalová, Joseph Peter Baraka, Václav Mik, Radek Jorda, Lei Luo, Hao Shao, Vladimír Kryštof
Cyclin dependent kinases (CDKs) constitute a family of serine/threonine protein kinases that form active complexes with corresponding cyclins to regulate cell cycle transitions and transcription [1]. CDK7 associates with cyclin H and MAT1 to form the CDK-activating kinase (CAK) complex, directing cell cycle transitions by phosphorylating the T-loop of cell cycle CDKs, such as CDK1, 2, 4 and 6 [2,3]. CDK7 is also a component of the general transcription factor IIH (TFIIH), facilitating transcription initiation by phosphorylating the C-terminal domain (CTD) heptapeptide repeats of RNA polymerase II (RNAP II) at Ser5 and Ser7 residues [4,5]. In addition, CDK7 phosphorylates CDK9, a component of positive transcription elongation factor b (P-TEFb), which in turn, phosphorylates the Ser2 residue of the RNAP II CTD to allow productive transcription elongation [6].
Response of murine neural stem/progenitor cells to gamma-neutron radiation
Published in International Journal of Radiation Biology, 2022
Galina A. Posypanova, Marya G. Ratushnyak, Yuliya P. Semochkina, Alexander N. Strepetov
Stimulation of stem cell proliferation after exposure to low doses of ionizing radiation has been reported in several works (Liang et al. 2011; Yang et al. 2017; Schröder et al. 2019). Liang et al. (2011) found the stimulation of proliferation of rat mesenchymal stem cells (MSCs) one day after X-ray irradiation at doses of 20–100 mGy. The dependence was non-linear; the maximum level of stimulation was observed at doses of 50 and 75 mGy. The authors showed that the stimulation of proliferation is associated with the activation of the MAPK/ERK signaling pathway. Irradiation at a dose of 50 mGy stimulated the incorporation of BrdU into cellular DNA (Schröder et al. 2019); at a dose of 75 mGy, it led to an increase in the proportion of cells in the S-phase of the cell cycle after 24 h and to a significant increase in the number of cells after 96 h of cultivation (Yang et al. 2017). In the last work, the authors investigated the phosphorylation of proteins associated with the cell cycle and showed an increase in the phosphorylation of Rb and CDK1 24 h after irradiation. Phosphorylation of Rb in the middle of the G1 phase (by cyclin D-Cdk4 or cyclin D-Cdk6 complex) leads to the release of transcription factors E2F-DP from the complex with Rb and their activation. Phosphorylation of CDK1 in complex with cyclin B at threonine-161 by CDK-activating kinase is necessary for the activation of CDK1 and the transition of the cell from the G2 phase to mitosis (Shen and Huang 2012).
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
The stability, intracellular localization and association of cyclin D with CDK4/6 are regulated through a variety of pathways. The inhibitor of CDK4 (INK4) proteins (p16INK4A, p15INK4B, p18INK4C, p19INK4D) weaken the binding interaction between D-type cyclins and CDK4/6 by directly suppressing the CDK catalytic domains to inhibit kinase activity [5]. Additionally, the CDKN2A gene, which encodes p16INK4A, is the most frequently deleted locus in human cancers [3]. Stress conditions induce INK4 expression which leads to inhibition of CDK4/6 through the disruption of cyclin-CDK binding. This is exemplified by studies which demonstrated that stress induced by cellular aging and oncoprotein activation induce the expression of p16INK4A and p15INK4B resulting in cell cycle arrest [6]. Additionally, CDK4/6 undergo phosphoregulation through CDK-activating kinase (CAK) and cell division cycle 25 (Cdc25) phosphatases [7].