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CDK Inhibitors in Leukemia and Lymphoma
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
The transcription of eukaryotic protein-encoding genes is controlled by ribonucleic acid polymerase II (RNAPII) in the elongation phase. Interplay between negative and positive elongation factors (referred to as N-TEF and P-TEF, respectively) regulates the elongation potential of RNAPII. P-TEFb is the first and only known component of P-TEF. The cyclin T-CDK9 complex (P-TEFb) phosphorylates and activates the carboxy-terminal domain (CTD) of RNAPII preferentially at Ser2 and most likely at Ser5 as well (6), leading to promotion of transcriptional elongation, events sensitive to 5,6-Dichloro-1-β-D-ribofuranosylbenzimidaloe (DRB), a well-known inhibitor of transcriptional elongation (6). In addition, CDK9 may act as a multifunctional kinase rather than solely as a CTD kinase (or transcriptional CDK) in cell differentiation, apoptosis, and cell cycle regulation pathways. For example, the cyclin T-CDK9 complex phosphorylates pRb (7). In addition, the initiation phase of transcription has been linked to CDK7 activation/initiation (8). An important implication of these findings is that in addition to the effects on cell cycle progression, disruption of CDK function can have profound effects on gene transcription.
Personalized Medicine in Lung Cancer
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
Daniela Morales-Espinosa, Silvia Garcá-Román, Rafael Rosell
Many drugs target CDKs as these are deregulated in cancer cells. Their inhibitors compete with ATP for the enzyme active site. Therefore, CDK inhibition results in RNPII hypophosphorylation.51 The most commonly targeted CDKs are CDK7, CDK8 and CDK9. CDK7 is a component of basal transcription factor TFIIH that phosphorylates Serine 5 and 7 in the C-terminal domain (CTD) of the RNPII, which is important for promoter escape and recruitment of mRNA processing machinery during transcription.52 CDK9 is also a component of P-TEFb, which, similar to CDK7, phosphorylates CTD of RNPII at serine 2 for transcription elongation.53, 54 The same activity is observed with the CDK8 kinase, which phosphorylates CTD of RNPII, resulting in inhibition of transcription initiation complex.
Small molecule inhibitors of cyclin-dependent kinase 9 for cancer therapy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Cyclin-dependent kinases (CDKs) form heterodimers with a specific family of proteins called cyclins. These functional CDK–cyclin complexes regulate cell cycle progression and gene transcription1. CDK9 is a member of the CDK family; it dimerises with cyclin T to form the positive transcription elongation factor b (p-TEFb) complex2,3. This complex stimulates transcription elongation through phosphorylation of the C-terminus domain (CTD) subunit of RNA polymerase II at Ser24. CDK9 plays a vital role in controlling the transcription of a number of genes, including Myc, a proto-oncogene that regulates processes required for cell growth and cell cycle progression, and Mcl-1, an anti-apoptotic member of the Bcl-2 family that enhances cell survival5. Therefore, CDK9 inhibition reduces messenger RNA (mRNA) transcription and prevents the expression of target genes (e.g. Myc and Mcl-1), which together regulate proliferation and cancer cells survival.
Emerging roles of noncoding RNAs in T cell differentiation and functions in autoimmune diseases
Published in International Reviews of Immunology, 2019
RN7SK RNA has been suggested to repress protein kinase P-TEFb, which is composed of Cdk9/cyclin T1 heterodimer, and found to regulate CD4+ T cell activation and differentiation. Overexpression of RN7SK RNA was shown to downregulate P-TEFb complex in CD4+ T cells, and thus contribute to the disease pathogenesis in MS [49]. TUG1 is required for normal retinal development and is a direct downstream target of p53 and is active in early stages of MS [49, 50]. NEAT1 is induced by the activation of TLR3-p38 signaling pathway and promotes the transcriptional activation of IL-8 which causes excessive formation of paraspeckles [51]. Paraspeckles are the nuclear bodies containing several protein factors such as splicing factor proline/glutamine-rich (SFPQ), Non-POU Domain Containing Octamer-Binding (NONO), which binds directly to NEAT1. NEAT1 on binding re-locates SFPQ, NONO which results in enhanced transcription of IL-8 and paraspeckle formation contributing to MS [51]. IFNG-AS1 (Tmevpg1) is another lncRNA associated with MS as it is involved in the regulation of T lymphocytes [49].
Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints
Published in Expert Opinion on Investigational Drugs, 2019
S. Percy Ivy, Charles A. Kunos, Fernanda I. Arnaldez, Elise C. Kohn
A second set of CDKs, CDK7–CDK9 and CDK10–CDK13 have been shown to be involved in replication stress and are regulators of transcription. CDK9 is a component of the multiprotein complex TAK/P-TEFb, an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. CDK9 forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. Modulation of CDK9 activity seems to be a key contributor to epigenetic reprogramming and thus ripe for use in combination approaches Dinaciclib is being developed as a pluripotent CDK inhibitor, targeting CDK1, 2, 5, and 9. Early phase trials demonstrated that the most relevant toxicities include diarrhea, fatigue, and myelosuppression (NCT01624441). Preclinical data suggest that dinaciclib may have benefit, especially where cyclin E is upregulated [70]. Further data and preliminary clinical evidence are required to define a role in HGSOC therapy.