Review
New Insights into CDK Regulators: Novel Opportunities for Cancer Therapy

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Highlights

  • The cell cycle is a complex process that is controlled by multiple regulatory pathways that also integrate extracellular signals to govern cell growth and division.

  • Ribosomal proteins are key regulators of the cell cycle. Recent research studies confirmed the existence of a third class of cyclin-dependent kinase (CDK) inhibitors, besides CDK-interacting protein/kinase inhibitory protein (CIP/KIP) and inhibitor of kinase (INK) families, called ribosomal protein inhibiting CDKs (RPICs).

  • The new cell cycle regulators constitute valuable targets for precision medicine, through the identification of peptides or small molecules mimicking their CDK inhibitor activities, opening novel avenues for the treatment of cancer and aging-related diseases.

Cyclins and their catalytic partners, the cyclin-dependent kinases (CDKs), control the transition between different phases of the cell cycle. CDK/cyclin activity is regulated by CDK inhibitors (CKIs), currently comprising the CDK-interacting protein/kinase inhibitory protein (CIP/KIP) family and the inhibitor of kinase (INK) family. Recent studies have identified a third group of CKIs, called ribosomal protein-inhibiting CDKs (RPICs). RPICs were discovered in the context of cellular senescence, a stable cell cycle arrest with tumor-suppressing abilities. RPICs accumulate in the nonribosomal fraction of senescent cells due to a decrease in rRNA biogenesis. Accordingly, RPICs are often downregulated in human cancers together with other ribosomal proteins, the tumor-suppressor functions of which are still under study. In this review, we discuss unique therapies that have been developed to target CDK activity in the context of cancer treatment or senescence-associated pathologies, providing novel tools for precision medicine.

Section snippets

Cell Cycle and CDK Regulators: A Never-Ending Story

Cell growth and cell division require a highly regulated series of events, called the cell cycle. Over the past few decades, key components of this machinery were identified, mainly through genetic and biochemical studies in yeast. The cell cycle comprises four distinct phases: growth phase 1 (G1), DNA replication or synthesis phase (S), growth phase 2 (G2), and mitotic phase (M). Progression through these different phases is driven by cyclin-dependent kinases (CDKs) whose activities are

Ribosomal Proteins as an Emerging New Class of Cell Cycle Regulators

Ribosomal proteins (RPs) have a crucial role in cell cycle control. Ribosome synthesis and maturation is a process requiring hundreds of cofactors and occurs in the cytoplasm as well as in the nucleolus [23]. This vital process requires the coordination of three major polymerases and is tightly regulated by numerous oncogenes and tumor suppressors to accommodate the cellular demand for growth or cell cycle arrest [24,25]. 47S rRNA is synthetized in the nucleolus by RNA polymerase I and is

RPs as Targets in Cancer and Senescence-Associated Diseases

Given the important roles of CDKs in cancer progression as well as in other diseases, such as atherosclerosis, type 2 diabetes, sarcopenia, and obesity [73], extensive efforts are underway to identify novel molecules that modulate, positively or negatively, their activity. A series of small molecules that mimic CKI activities were developed to target hyperproliferative tumor cells. Flavopiridol and roscovitine were among the first generation of compounds inhibiting CDKs, but their lack in

Concluding Remarks

For more than 30 years, understanding aberrant cell cycle control in tumor cells has been a major focus of cancer research. Evasion of growth suppressors and deregulation of checkpoints are considered hallmarks of cancer. The control of the cell cycle is complex and numerous regulators have been identified, including endogenous proteins as well as synthetic compounds, such as small-molecule inhibitors. Undoubtedly, the control of cell cycle progression is not limited to the well-known

Acknowledgments

M.B. was supported by a Télévie fellowship (FNRS, Belgium). V.B. acknowledges grants from the Canadian Institutes of Health Research (CIHR, Canada) MOP-97932 and PJT-152937. G.F. acknowledges CCSRI (Canadian Cancer Society Research Institute: 704223) and the CIBC Chair for Breast Cancer Research at the CR-CHUM.

Declaration of Interests

We have no conflicts of interest to declare.

References (120)

  • X. Zhou

    Ribosomal protein S14 negatively regulates c-Myc activity

    J. Biol. Chem.

    (2013)
  • F. Wan

    Ribosomal protein S3: a KH domain subunit in NF-kappaB complexes that mediates selective gene regulation

    Cell

    (2007)
  • R. Srivas

    A network of conserved synthetic lethal interactions for exploration of precision cancer therapy

    Mol. Cell

    (2016)
  • G. Yahya

    A Whi7-anchored loop controls the G1 Cdk-cyclin complex at start

    Mol. Cell

    (2014)
  • J. Yang

    Systematic determination of human cyclin dependent kinase (CDK)-9 interactome identifies novel functions in RNA splicing mediated by the DEAD Box (DDX)-5/17 RNA helicases

    Mol. Cell. Proteomics

    (2015)
  • M. Moorthamer et al.

    Identification of ribosomal protein L34 as a novel Cdk5 inhibitor

    Biochem. Biophys. Res. Commun.

    (1999)
  • G. Elgar et al.

    Tuning in to the signals: noncoding sequence conservation in vertebrate genomes

    Trends Genet.

    (2008)
  • Y.A. Ko et al.

    Epigenomics: the science of no-longer-junk DNA. Why study it in chronic kidney disease?

    Semin. Nephrol.

    (2013)
  • S. He et al.

    Senescence in health and disease

    Cell

    (2017)
  • J. Lu

    Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of hormone-receptor positive advanced breast cancer

    J. Hematol. Oncol.

    (2015)
  • M.J. Bywater

    Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53

    Cancer Cell

    (2012)
  • R.A. Saxton et al.

    mTOR signaling in growth, metabolism, and disease

    Cell

    (2017)
  • S. Shi

    Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma

    Biomed. Pharmacother.

    (2021)
  • D.A. Nalawansha et al.

    PROTACs: an emerging therapeutic modality in precision medicine

    Cell Chem. Biol.

    (2020)
  • S. Rana

    Selective degradation of CDK6 by a palbociclib based PROTAC

    Bioorg. Med. Chem. Lett.

    (2019)
  • L. Gonzalez et al.

    RINGO/Speedy proteins, a family of non-canonical activators of CDK1 and CDK2

    Semin. Cell Dev. Biol.

    (2020)
  • M. Frontini

    The CDK subunit CKS2 counteracts CKS1 to control cyclin A/CDK2 activity in maintaining replicative fidelity and neurodevelopment

    Dev. Cell

    (2012)
  • P. Nurse

    Genetic control of cell size at cell division in yeast

    Nature

    (1975)
  • L.H. Hartwell

    Genetic control of the cell-division cycle in yeast. I. Detection of mutants

    Proc. Natl. Acad. Sci. U. S. A.

    (1970)
  • M.G. Lee et al.

    Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2

    Nature

    (1987)
  • D.K. Morrison

    MAP kinase pathways

    Cold Spring Harb. Perspect. Biol.

    (2012)
  • R.J. Duronio et al.

    Signaling pathways that control cell proliferation

    Cold Spring Harb. Perspect. Biol.

    (2013)
  • M.V. Blagosklonny

    Cell senescence and hypermitogenic arrest

    EMBO Rep.

    (2003)
  • Y. Gu

    Inhibition of CDK2 activity in vivo by an associated 20K regulatory subunit

    Nature

    (1993)
  • K. Polyak

    p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest

    Genes Dev.

    (1994)
  • S. Matsuoka

    p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene

    Genes Dev.

    (1995)
  • M.H. Lee

    Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution

    Genes Dev.

    (1995)
  • G.J. Hannon et al.

    p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest

    Nature

    (1994)
  • M. Serrano

    A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4

    Nature

    (1993)
  • K.L. Guan

    Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function

    Genes Dev.

    (1994)
  • H. Hirai

    Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6

    Mol. Cell Biol.

    (1995)
  • F.K. Chan

    Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4

    Mol. Cell Biol.

    (1995)
  • C.J. Sherr et al.

    CDK inhibitors: positive and negative regulators of G1-phase progression

    Genes Dev.

    (1999)
  • D. Ruggero et al.

    Does the ribosome translate cancer?

    Nat. Rev. Cancer

    (2003)
  • R.J. White

    RNA polymerases I and III, growth control and cancer

    Nat. Rev. Mol. Cell Biol.

    (2005)
  • S. Klinge et al.

    Ribosome assembly coming into focus

    Nat. Rev. Mol. Cell Biol.

    (2019)
  • S.N. Slimane

    Ribosome biogenesis alterations in colorectal cancer

    Cells

    (2020)
  • X. Zhou

    Ribosomal proteins: functions beyond the ribosome

    J. Mol. Cell Biol.

    (2015)
  • F. Lessard

    Ribosomal proteins control tumor suppressor pathways in response to nucleolar stress

    Bioessays

    (2019)
  • R.Y. Ebright

    Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis

    Science

    (2020)
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    Current address: Centre de Recherche sur le Cancer de l’Université Laval, Québec, QC, Canada

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