Cell cycle-related kinases

Abstract

Cyclin proteins are regulatory subunits of a holoenzyme, which together with CDKs, phosphorylate key substrates to modulate cellular physiology and drive cell cycle progression. At least 13 human CDKs have been identified that have different functions that contribute to the appropriate coordination of cell cycle transitions, as well as other processes (e.g. transcription). For example, cyclin D1 and assembled CDK complexes phosphorylate and inactivate the retinoblastoma protein and thereby promote DNA synthesis (Arnold and Papanikolaou J Clin Oncol 23(18):4215-24, 2005). Cyclin D1 kinases also phosphorylate and inactivate the NRF1 transcription factor, thereby inhibiting mitochondrial biogenesis (Sakamaki T, Casimiro MC, Ju X, Quong AA, Katiyar S, Liu M, et al. Cyclin D1 determines mitochondrial function in vivo. Mol Cell Biol. 2006;26(14):5449-69; Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, et al. Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc Natl Acad Sci U S A. 2006;103(31):11567-72). Physiological stresses and mitogenic signaling pathways converge on the activity of cyclin CDK complexes to control cell cycle transitions. For example,multiple cyclin CDK complexes are targets of cell cycle checkpoints controlling G1/S and G2/M transitions, thereby protecting the cell from erroneous DNA replication, ensuring the integrity and precision of cellular division (Pestell. Am J Pathol 183(1):3-9, 2013). Conversely, mitogen-mediated passage through the restriction point in G1 is controlled by the cyclin families, the cyclin D family (D1, D2, and D3), and the cyclin E family (E1 and E2). Due to the central role of CDKs in controlling proliferation, they represent important targets for cancer therapy.