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Review
. 2025 Jan 13;10(1):11.
doi: 10.1038/s41392-024-02080-z.

Cyclin-dependent protein kinases and cell cycle regulation in biology and disease

Ilenia Pellarin #  1 , Alessandra Dall'Acqua #  1 , Andrea Favero  1 , Ilenia Segatto  1 , Valentina Rossi  1 , Nicole Crestan  1 , Javad Karimbayli  1 , Barbara Belletti  1 , Gustavo Baldassarre  2
Affiliations
Review

Cyclin-dependent protein kinases and cell cycle regulation in biology and disease

Ilenia Pellarin et al. Signal Transduct Target Ther. .

Abstract

Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as the kinases able to drive cell division. In reality, the human genome contains 20 different CDKs, which can be divided in at least three different sub-family with different functions, mechanisms of regulation, expression patterns and subcellular localization. Most of these kinases play fundamental roles the normal physiology of eucaryotic cells; therefore, their deregulation is associated with the onset and/or progression of multiple human disease including but not limited to neoplastic and neurodegenerative conditions. Here, we describe the functions of CDKs, categorized into the three main functional groups in which they are classified, highlighting the most relevant pathways that drive their expression and functions. We then discuss the potential roles and deregulation of CDKs in human pathologies, with a particular focus on cancer, the human disease in which CDKs have been most extensively studied and explored as therapeutic targets. Finally, we discuss how CDKs inhibitors have become standard therapies in selected human cancers and propose novel ways of investigation to export their targeting from cancer to other relevant chronic diseases. We hope that the effort we made in collecting all available information on both the prominent and lesser-known CDK family members will help in identify and develop novel areas of research to improve the lives of patients affected by debilitating chronic diseases.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
From the cell discovery to the CDKs targeting: a subjective timeline. Timeline of milestone events leading to the discovery, research and development related to cyclin dependent kinases (CDKs), cyclins and cell cycles regulators. In this long journey many more milestones could be identified, and this timeline represents our personal point of view. See text for references; caption of the original cork picture, described in “Micrographia” by Robert Hooke (1665), is reported in the Figure. (Adapted from “Timeline (7 segments, Horizontal), by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates)
Fig. 2
Fig. 2
Generation and Analysis of the Phylogenetic Tree of Human Full-Length CDKs. The phylogenetic tree of human full-length CDKs was generated using the ggtree R package. Homology among the protein sequences was evaluated using Multiple Sequence Alignment (MSA) analysis, with CDK12 and CDK13, the longest CDKs, serving as references. The MSA reference number denotes the alignment position. Different amino acids in the protein sequences are color-coded, and gaps are introduced to properly separate conserved amino acid regions among CDKs (indicated by horizontal lines/spaces). The Serine/Threonine protein kinase domain is well conserved across all CDKs, although they show significant divergence in the lengths of their N-terminal and C-terminal extensions. On the right, a schematic representation of CDKs is provided, highlighting the kinase domain and indicating the amino acid length of each CDK. (Created with BioRender.com)
Fig. 3
Fig. 3
Cell Cycle Progression via EGFR and Receptor Tyrosine Kinase Signaling. EGFR stimulation promotes the activation of the CycC-CDK3 complex, enabling the cell to exit quiescence (G0) and enter the G1 phase by priming RB phosphorylation. Activation of various Receptor Tyrosine Kinases (RTKs) can similarly promote G1 progression through signal cascades involving RAS-GTP and its downstream RAF/MEK/ERK and PI3K/AKT/mTOR pathways. These signaling cascades lead to the formation and activation of CycD-CDK4/6 complexes and their translocation to the nucleus. In the nucleus, CycD-CDK4/6 complexes further phosphorylate RB. The inhibition of RB allows the accumulation of E2F on DNA, promoting the transcription of genes essential for cell cycle progression and DNA replication. Subsequently, the activation of the CycE-CDK2 complex drives the transition from G1 to S phase by hyper-phosphorylating RB, enabling cell cycle progression independently of growth factor stimuli (bypassing the restriction point). The accumulation of CycA and the displacement of CycE from the CycE-CDK2 complex facilitate the formation of the CycA-CDK2 complex, which drives S phase entry, progression, and DNA synthesis. Following faithful DNA replication, the CycA-CDK1 complex triggers entry into mitosis. This is followed by the formation and activation of the CycB-CDK1 complex, which is necessary for the completion of proper cell division. The roles of activating proteins (such as CAK and CDC25A/B/C) and inhibitory proteins (such as CDK inhibitors, WEE1, and MYT1) on specific cyclin-CDK complexes are indicated by black arrows. Abbreviations used: RTKs Receptor Tyrosine Kinase, CAK complex CDK Activating Kinase complex, CycA cyclin A, CycB cyclin B, CycC cyclin C, CycD cyclin D, CycE cyclin E, CDC25 Cell Division Cycle 25. (Adapted from “Cell Cycle Checkpoints”, “RAS Pathway”, by BioRender.com (2024)
Fig. 4
Fig. 4
CDK/cyclin complexes roles in the regulation of the transcriptional cycle. a Stepwise Assembly of the Pre-Initiation Complex (PIC) and RNA Polymerase II (RNA pol II) recruitment. The assembly of PIC and the recruitment of RNA pol II is a highly coordinated process essential for initiating RNA transcription. The process begins with the TATA-binding protein (TBP) subunit of TFIID binding to the promoter region of the DNA. This binding is stabilized by the interaction with TFIIA. Next, TFIIB is recruited, which subsequently engages with the RNA pol II-TFIIF complex. Following this, TFIIE associates with RNA pol II, facilitating the binding of the TFIIH complex. The TFIIH complex includes the cyclin-dependent kinase-activating kinase (CAK) complex, which is composed of CDK7, MAT1, and cyclin H. This sequential assembly of the PIC is critical for DNA melting and the phosphorylation of the C-terminal domain (CTD) of RNA pol II, both of which are crucial steps for initiating RNA transcription. b The Role of Transcriptional CDKs in the different stages of transcription: 1. PIC Assembly and Initiation: the phosphorylation of RNA Pol II CTD at Ser5 and Ser7 by CDK7 promotes initiation, promoter clearance, and co-transcriptional 5’-end capping. The CDK8 kinase module (CKM, composed of CDK8, cyclin C, Med12, and Med13) associates with the core Mediator complex, to associate activators to RNA Pol II. When not associated with RNA Pol II, CKM can negatively modulate CDK7 activity by phosphorylating cyclin H, inhibiting transcription initiation. Additionally, CDK8 function can be positively regulated by p21. 2. Promoter-Proximal Pausing and Pause Release: this process involves the exchange of TFIIE for the elongation factor DSIF, which recruits NELF to establish a pause 50-100 bp downstream of the Transcription Start Site (TSS). CDK9/cyclin T, also known as positive Transcription Elongation Factor b (P-TEFb), phosphorylates components of the paused complex to relieve pausing. The interaction of CDK9 with BRD4 is enhanced by acetylation of cyclin T1 by p300 and phosphorylation of CDK9, facilitating the release of P-TEFb from the inhibitory factor 7SK snRNP. 3. Elongation and Splicing: Pol II CTD Ser2 is phosphorylated by CDK9 and/or CDK12/13 to promote productive elongation and splicing events. CAK mediates CDK9 and CDK12/13 activation through T-loop phosphorylation. Additionally, CKM recruits P-TEFb during elongation, and its dephosphorylation by PP2A further enhances elongation. CDK11/CycL and CDK10/CycM can also phosphorylate transcription and splicing factors to promote splicing. 4. Termination and translation: RNA cleavage and polyadenylation factors are phosphorylated by CDK9 and/or CDK12/13, facilitating cleavage, polyadenylation of the pre-mRNA, and Xrn2-dependent termination. CDK12/CycK phosphorylates 4E-BP1, promoting translation of specific genes in the cytoplasm. c. Regulation of Pol II CTD Phosphorylation During Transcription. The phosphorylation state of the RNA pol II CTD is dynamically regulated throughout the transcription cycle. As transcription progresses from initiation at the TSS, through elongation in the gene body to termination at the polyadenylation site (Poly A), distinct phosphorylation marks are added or removed to modulate specific transcriptional functions. This regulation is crucial for coordinating the various stages of transcription, including initiation, elongation, RNA processing, and termination. See the text for detailed references. (Created with BioRender.com and Adapted from “Eukaryotic Gene Regulation - Transcriptional Initiation”, by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates)
Fig. 5
Fig. 5
Dynamics of CDK5 activation in comparison with cell-cycle CDKs. a In a physiological context, p35 is membrane-bound due to its myristoylation signal, which recruits and activates CDK5. The binding of CDK5 to this co-factor is essential for its kinase activity. In various pathologies, the proteolytic cleavage of p35 into p25 by calpain is dysregulated, increasing the stability of p25 and leading to CDK5 hyperactivation. b, c The regulation of CDK5 (c), an atypical CDK, differs significantly from the classic regulation of cell-cycle CDKs (b), despite its high similarity to CDK1 and CDK2. For cell-cycle CDKs, the binding of cyclins confers low activity, which requires CAK phosphorylation for full activation. Unlikely, the activation of CDK5 does not require cyclins or phosphorylation upon co-factor binding. The inhibitory phosphorylation on Thr14 inside the binding cleft, which in CDK2 is mediated by WEE1/MYT1, has been poorly investigated in CDK5. Conversely, phosphorylation on Thr15, which inactivates CDK2 (also mediated by WEE1/MYT1 for CDK2 and not well studied for CDK5), activates CDK5. Additionally, while Thr160 phosphorylation is crucial for CDK2 activation, the corresponding phosphorylation site in CDK5 (Ser159) is likely inhibitory. CDKs full and partial activation are indicated by red and dashed red star respectively. Created with BioRender.com
Fig. 6
Fig. 6
The Role of CDKs in neurodegenerative diseases. Involvement of various CDKs in neurodegeneration, categorized by the different stages that lead to the onset and progression of neurodegenerative diseases. The figure specifies whether the role of each CDK is direct or indirect. CDK2 and CDK5 are the only CDKs directly involved in neurodegenerative diseases by regulating neuronal cell death through alteration of ROS species and accumulation of aggregated proteins,,,,–,– being involved in the pathological aggregation of proteins through the regulation of tau phosphorylation,–,, and participating in the appearance of cytoskeletal abnormalities.,, Many other CDKs are indirectly involved in upstream processes, which subsequently contribute to the progression of neurodegenerative diseases. This distinction helps in understanding the specific and broader impacts of CDKs on the development and advancement of neurodegenerative pathologies.,– Created with BioRender.com
Fig. 7
Fig. 7
The Role of CDKs in non-cancer diseases. Involvement of CDKs in various non-cancer pathologies, categorized into three macro-categories: inflammatory conditions, autoimmune diseases, and metabolic diseases. While these categories provide a structured overview, there is some overlap among them, reflecting the complex interplay of CDKs in these conditions. The CDKs involved in the pathogenesis of rheumatoid arthritis mainly drive the release of metalloproteinases from fibroblast-like synoviocytes (FLSs) and the proliferation of FLSs.,– In the systemic lupus erythematosus the inhibition of certain CDKs ameliorates the immune components of the disease.,– CDK4 is the only CDK involved in the pathogenesis of mellitus diabetes type I, influencing the development and the proliferation of pancreatic β-cells.– Instead, many CDKs play a role in the pathogenesis of type II diabetes, regulating β-cells proliferation, metabolism and apoptosis.,,,,, Different CDKs participate in the regulation of adipogenesis and obesity, regulating the differentiation of preadipocytes in mature adipocytes, tuning the expression of adipogenic genes, consequently leading to fat accumulation.,–,– Regulation of the fibrotic process by CDKs relay on their ability to regulate fibroblasts behavior and ECM remodeling, that have been investigated in CDK4, CDK5 and CDK6.,, Only few reports link CDKs to the pathogenesis of allergies., In psoriasis CDKs, by altering the homeostasis of several pathogenic cytokines, promote inflammation and proliferation of different cells types.,,, Created with BioRender.com
Fig. 8
Fig. 8
Milestones in CDK inhibitors development: from generation to approval. The timeline shows the discovery of the first pan-CDK inhibitor Flavopiridol, followed by the development of second generation multi-CDK inhibitors, here simplified by the sole representation of Dinaciclib. The development of the five CDK4/6 specific inhibitors approved for the use in clinics are reported (Palbociclib, Abemaciclib, Ribociclib, Trilaciclib and Dalpiciclib). For each of them, the key trials that have eventually led to their agency approval (FDA, EMA or NMPA) are indicated. More details on discovery, preclinical studies and clinical trials on these drugs can be found in the text. FDA: Food and Drug Administration; EMA: European Medicines Agency; NMPA: National Medical Products Administration. (Adapted from “Timeline (7 segments, Horizontal), by BioRender.com (2024). Retrieved from https://app.biorender.com/biorender-templates)
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