If the Present Reevaluates the Past: Deciphering the Cell Division Cycle for Advancement in Cancer Therapy

Dear Colleagues,

The proper development and homeostasis of tissues and organs at the cellular level are ensured by a finely and timely regulated progression of the cell division cycle, which requires the perfectly harmonized activity of numerous protein kinases/phosphatases and regulatory proteins. Among them, cyclin-dependent kinases (CDK)s with their modulatory partners, cyclins, represent the major players acting with switch-like behavior to turn on cell growth, through the control of chromatin replication and condensation, gene transcription, assembly of the mitotic spindle, and proper cytodieresis. These holoenzymes exist in distinct configurations or stable steady states, defined by various phosphatases and kinases that render the on/off switch rapid.

This system is provided with additional levels of regulation. Particularly, two distinct families of CDK inhibitor (CDKI) proteins have been identified so far:  the INK4 (INhibitors of CDK4/6) family, comprising p16^INK4a, p15^INK4b, p18^INK4c, p19^INK4d, and the CIP (CDK Interacting Proteins)/KIP (Kinase Inhibitory Proteins) family, consisting of three members, p21^Cip1, p27^Kip1, and p57^Kip2, with a broader range of CDK targets. These small proteins play key roles in restraining proliferation during development, differentiation, and in response to cellular stresses and treatments. Although their activities appear in some cases redundant, each INK4 or Cip/Kip family member can be only partially substituted by the other family components, indicating that they have distinct and specific biological functions.

Through the years, this simplified view of the cell cycle machinery has grown in complexity. So far, about 20 CDKs have been identified, and a similar number of cyclins has been reported, increasing the possibilities of reciprocal heterodimer combination. A current vision considers that these key proteins may participate in a variety of dynamically assembled multimolecular complexes showing specific cellular functions.

Indeed, new roles of CDKs and of their regulating partners have been recently identified, not directly related to cell cycle progression. Also, an ample body of studies is dedicated to the elucidation of the signal transduction pathways impinging on the intrinsic mechanism of cell cycle control.

An increasing number of researches has highlighted the strong CDKI promiscuity. Several of them are Intrinsically Unstructured proteins (IUP)s, therefore endowed with a high conformational flexibility which allows them to have numerous interactors and play many different activities. Accordingly, they have been involved in different cellular processes, such as CDK inhibition but also promotion of cyclin/CDK complex assembly and allosteric regulation, DNA replication and fine-tuning gene transcription, cytoskeleton dynamics and motility modulation, as well as apoptosis and autophagy control.

The importance of cell cycle regulatory proteins clearly emerges from the wide implications of their deregulation in human health and diseases. As a matter of facts, metabolic perturbations, uncontrolled cell proliferation and motility, development and progression of human malignancies might be associated to cell cycle abnormalities. The inhibition of the cell cycle kinases, particularly Cyclin Ds–CDK4/6 targeting molecules, is now part of the standard treatments of breast cancer, pancreatic adenocarcinoma, and other types of cancer.

More complex is the comprehension of CDKI role in cancer. The genes encoding some of these proteins have been recognized as oncosuppressors (INK4A) or as haploinsufficient tumor suppressors (CDKN1B). However, mechanistic studies have also revealed an ambiguous behavior, which in some cases may result in oncogenic functions closely related to cancer progression and metastatization.

The precise knowledge of the structures and mechanisms of action of these inhibitors might provide more efficient models in pharmaceutical engineering for CDK-targeted therapies, that are an appealing aspect of promising preclinical and clinical studies in human cancer.

In this Special Issue of Cells, we invite contributions, in the form of either original research articles or reviews, focusing on the mechanistic and functional relationships between the cell cycle regulating machinery and cancer. The content of the manuscripts should be relevant to the topics listed below, although papers on other related issues may be accepted.

 

Cell cycle protein roles in cell proliferation, gene transcription, DNA repair, ageing, senescence, and cell death

Cell cycle regulators in embryonic and postnatal development

Cell cycle regulator alteration in cancer

Cell cycle regulators in cell movement and metastatization

Cell cycle-related proteins as therapy targets

Drug discovery in cell cycle inhibition

Role of cell cycle regulators in metabolic control

Cell cycle-related proteome and epigenome

Prof. Dr. Adriana Borriello
Prof. Dr. Fulvio della Ragione
Dr. Debora Bencivenga
Guest Editors

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