Cell Cycle Proteins as Promising Targets in Cancer Therapy

Dear Colleagues,

The cell cycles in eukaryotic cells are dynamically regulated by extrinsic, growth factor-induced, mitogenic, and intrinsic signals from proteins that are involved in monitoring genomic integrity. The cell cycle progresses through four distinct phases, namely G0/G1, S, G2, and M phases. Different complexes of cyclin-dependent kinases (CDKs), their cyclin partners, and the CDK inhibitor (CDKI) proteins regulate each of the cell cycle phases. CDKIs consist of two families of proteins—the CIP/KIP family (p21/WAF1/CIP1, p27KIP1) and INK4 family (p16INK4A and alternatively spliced ARF, p15INK4B, p18INK4C, and p19INK4D). Cyclin D-CDK4/6 complex regulates canonical cell cycle progression by activating retinoblastoma (RB1)-E2F signaling to facilitate progression from G1 into S phase, DNA replication, chromatin structure and chromosome segregation, and the spindle assembly checkpoint (SAC). Activated E2F signaling also stimulates the transcription of cyclins E1 and E2, which are a complex with CDK2. Cyclin E-CDK2 further activates RB/E2F signaling in a feed-back manner to ensure proper transition through S phase. Transition from S phase to G2, and progression through G2 to the mitotic (M) phase is controlled by different cyclin A or cyclin B-CDK1 complexes, along-with other proteins such as aurora A and B kinases and polo-like kinases (PLK1). Proteins such as ATM/ATR kinases that trigger cell cycle arrest sense perturbations in genomic integrity and DNA damage. DNA damage-induced checkpoints regulate activities of different CDK complexes to halt cell cycle progression and to allow time for DNA repair. Checkpoint kinase 2 (CHK2) and p53 activation occurs so as to arrest cells in the G1 phase, while CHK1 activation functions to arrest cells in the S or G2 phases.

Many human cancers harbor amplified genes encoding Cyclin D1, CDK4/6, and/or Cyclin E1, which function as drivers of oncogenesis, while the mutation and/or deletion of RB and the deletion of the p16INK4A and p14ARF locus or the repression of these CDKI expressions through promoter methylation also occurs in human cancers. Although CDK2 mutations are not encountered in human cancers, CDK1 function is essential for cell cycle progression. CDK1-Cyclin B1 activity is required for dynamic control of the G2 phase and transition to the M phase. As many CDKs are frequently and aberrantly activated in human cancers, a rationale for targeting CDKs for cancer therapy has emerged that has culminated into the current clinical use of pharmacological inhibitors of CDK4/6 kinases, while a number of pharmacological inhibitors of CDKs, CHK1, PLK, and aurora kinases are being tested in clinical trials. 

With this Special Issue, we kindly invite our colleagues to submit their latest research findings or reviews covering basic signaling and translational aspects of cell cycle proteins. The topics may include new knowledge of the mechanisms and pathways involved in the regulation/control of cell cycles under physiological and pathophysiological conditions, as well as new knowledge of the regulation of mediators/transducers of cell cycles in cancer cells in in vitro and in vivo models. Additionally, papers describing novel inhibitors that target cell cycle transducers in basic and/or clinical settings are welcome. We believe this Special Issue will offer a snapshot of the current knowledge of the cell cycle proteins, as well as their promise and potential for cancer therapy, while serving as a worthwhile resource for researchers worldwide wanting to deepen their knowledge in this field.

We look forward to your contributions and will be happy to discuss your suggestions.

Prof. Arun K. Rishi
Guest Editor

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• cyclins
• cyclin-dependent kinases
• Rb/E2F proteins
• cyclin-dependent kinase inhibitors
• check-point kinases