The role of cyclin and cyclin-dependent kinases in the occurrence of cancer
The role of cyclin and cyclin-dependent kinases in the occurrence of cancer
Samaneh Alijanian,1,*
1. Msc of Molecular Genetic Department of Genetics, Zanjan Branch, Islamic Azad University, Zanjan, Iran.
Introduction: Several human cancer cell types exhibit unchecked proliferative behavior, which is related to the dysregulation of Cdk/Cyclins. Mutations that hyperactivate Cdk activity, in contrast to those that inactivate checkpoint regulators, tumor suppressor genes, or CKIs, specifically enhance cell proliferation. Chemicals involved in the G1/S phase transition of the cell cycle are frequently altered in cancers. The majority of the time, it has been found that the Cdk4/6-cyclinD/INK4/pRb/E2F pathway is disrupted by mutations in the genes encoding these proteins or in its regulators. In medulloblastomas, squamous cell carcinomas, lymphomas, leukemias, and squamous cell carcinomas, Cdk6 gene amplification and overexpression have been shown. In some leukemias, Cdk6 overexpression can result in Cdk6 translocation, and in medulloblastoma, it may connect the TP53 and RB1 tumor suppressor pathways. Uncontrolled cell growth is caused by an imbalance between mitogenic stimuli and the control of the cell cycle, which is linked to the hyperphosphorylation of Rb brought on by the deregulation of Cdk4 and Cdk6/D-cyclins. The Cdk4/cyclin D/p16INK4a/pRb axis exhibits genetic changes in the majority of malignancies, according to research. Several malignancies, including melanoma, breast carcinoma, refractory rhabdomyosarcoma, osteosarcoma, glioma, and neuroblastoma, have been linked to dysregulations of Cdk4 as a result of gene amplification or overexpression. The goal of this study was to investigate the role of cyclin and cyclin-dependent kinases in the occurrence of cancer.
Methods: This study was on the role of cyclin and cyclin-dependent kinases in the occurrence of cancer from scientific databases such as Science Direct, Springer, Google Scholar, and PubMed.
Results: Cdks have important functions in the control of cell cycle and gene expression. Members of a distinct group of Cdks that regulate transcription depending on RNA polymerase II include Cdk7, Cdk8, and Cdk9 (RNA Pol II). Cdk8 and cyclin C are components of the Mediator complex, a transcriptional repressor. The Mediator complex suppresses the development of the pre-initiation complex by phosphorylating cyclin H to inhibit transcription factor II H (TFIIH) activity and RNA Pol II's carboxyl-terminal domain (CTD) to prevent it from binding to promoter DNA. The Cdk7/cyclin H holoenzyme, on the other hand, is a transcriptional activator. As part of TFIIH, Cdk7/cyclin H is brought to the proximal promoter during transcription initiation and phosphorylates RNA Pol II's CTD at the serine position to facilitate the capping enzyme's subsequent binding. In order to cause a change from transcription initiation to elongation, Cdk7/cyclin H, acting as a CAK, phosphorylates and activates Cdk9, the catalytic subunit of the positive transcription elongation factor b (P-TEFb). NELF and DSIF are phosphorylated by the active Cdk9/cyclin T to release the elongation complex from its paused state, and the CTD of RNA Pol II is phosphorylated at serine 2 sites to encourage progressive elongation of the transcript. In essence, Cdk-mediated phosphorylation of the CTD of RNA Pol II is what propels the sequential transition from pre-initiation to initiation to elongation. Cyclin D overexpression, genetic amplification, polymorphism, translocation, and alternative splicing are frequently linked to Cdk4 hyperactivity. One of the most prevalent tumor suppressor mutations in human malignancies, p16INK4a genetic inactivation leads to poor Cdk4 inhibition. Proteins involved in DNA replication, cell cycle progression, histone synthesis, and centrosome duplication are phosphorylated by Cdk2/cyclin E.
Conclusion: The combination of Cdk inhibitors and well-known cytotoxic drugs entered human trials based on the preclinical data that Cdk inhibitors can generally augment the anti-tumor actions of these agents in a dose- and sequence-dependent way. Prospective studies can aid in determining the best parameters for combination therapy, as well as determining whether highly selective versus pan-selective CDK inhibitors represent more effective treatments.