CDKs and CDK-Interacting Proteins/Kinase-Inhibitory Proteins in Human Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 December 2024) | Viewed by 794

Special Issue Editors


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Guest Editor
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
Interests: CIP/KIP proteins; p57Kip2; p27Kip1; p53; cell cycle regulation and cell differentiation; DNA damage; post-translational modifications; phosphorylation; kinase inhibitors; natural compounds; mesenchymal stem cells; cancer; Bechwidth-Wiedemann syndrome; IMAGe; Russell-Silver syndrome; hypoxia-related diseases; iron metabolism
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
Interests: cell division cycle alterations; cyclin dependent kinase inhibitors; tumor suppressor genes; cancer; altered hypoxia response
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy
Interests: cell division cycle alterations; cyclin dependent kinases and their inhibitors; protein post-translational modifications
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Decades of cell cycle-related research have led to unravelling the molecular mechanisms of cell cycle progression. In this context, cyclins, cyclin-dependent kinases (CDKs) and cyclin-dependent kinase regulators (CKRs) are undoubtedly primary cell cycle regulators. However, to date, the paradigm that they are only involved in ensuring correct cell division has been overcome. Indeed, it is consolidated that they have additional roles, such as transcriptional regulation, cell differentiation, DNA damage response, cytoskeleton remodeling, regulation of metabolism, cell death, stem cell fate, tissue regeneration and development. Despite more than 30 years of research, the full comprehension of their physiological roles is still lacking due to their multiplicity, tissue specificity and frequent functional overlapping. In parallel, even if the known pathological implications of their alterations range from the onset of human tumors to diseases related to growth, development and metabolism, new evidence suggests their involvement in a broader spectrum of genetic and epigenetic pathologies. Finally, in the era of target therapy, the comprehension of the regulatory mechanisms of cyclin/CDK complexes has made it possible to formulate new anti-cancer drugs targeting cell cycle proteins, as well as recognize the mechanisms underlying sensitivity and resistance to the related therapies, and develop alternative therapeutic strategies.

This Special Issue will cover and focus on the role of cell cycle-related proteins in health and various pathologies, particularly cancer and growth-related diseases, as well as emerging therapeutic strategies, and the role of cell cycle-related proteins as sensitizing or resistance factors in therapy.

Dr. Emanuela Stampone
Prof. Dr. Adriana Borriello
Dr. Debora Bencivenga
Guest Editors

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Keywords

  • Cell cycle
  • CDKs
  • cyclins
  • CIP/Kip proteins
  • INK4 family
  • p53
  • transcriptional regulation
  • DNA damage
  • cytoskeleton, metabolism, senescence, cell death, cell commitment and differentiation
  • stem cell
  • tissue regeneration
  • embryogenesis
  • development
  • growth-related diseases
  • cancer, sensitivity/resistance to therapy
  • target therapy

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Published Papers (1 paper)

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Research

30 pages, 4478 KiB  
Article
p27Kip1 and Tumors: Characterization of CDKN1B Variants Identified in MEN4 and Breast Cancer
by Debora Bencivenga, Emanuela Stampone, Jahanzaib Azhar, Daniela Parente, Waqar Ali, Vitale Del Vecchio, Fulvio Della Ragione and Adriana Borriello
Cells 2025, 14(3), 188; https://doi.org/10.3390/cells14030188 - 26 Jan 2025
Viewed by 361
Abstract
p27Kip1 is a key cell cycle gatekeeper governing the timing of Cyclin-dependent kinase (CDK) activation/inactivation and, consequently, cell proliferation. Structurally, the protein is largely unfolded, a feature that strongly increases its plasticity and interactors and enhances the number of regulated cellular processes. [...] Read more.
p27Kip1 is a key cell cycle gatekeeper governing the timing of Cyclin-dependent kinase (CDK) activation/inactivation and, consequently, cell proliferation. Structurally, the protein is largely unfolded, a feature that strongly increases its plasticity and interactors and enhances the number of regulated cellular processes. p27Kip1, like other intrinsically unstructured proteins, is post-translationally modified on several residues. These modifications affect its cellular localization and address p27Kip1 for specific interactions/functions. Several germline or somatic CDKN1B (the p27Kip1 encoding gene) mutations have been demonstrated to be associated with multiple endocrine neoplasia type 4 (MEN4), hairy cell leukemia, small-intestine neuroendocrine tumors, and breast and prostate cancers. Here, we analyzed the effect of four CDKN1B missense and nonsense mutations found in patients affected by MEN4 or cancers, namely, c.349C>T, p.P117S; c.397C>A, p.P133T; c.487C>T, p.Q163*; and c.511G>T, p.E171*. By transfecting breast cancer cell lines, we observed increased growth and cell motility for all the investigated mutants compared to wild-type p27Kip1 transfected cells. Furthermore, we discovered that the mutant forms exhibited altered phosphorylation on key residues and different localization or degradation mechanisms in comparison to the wild-type protein and suggested a possible region as crucial for the lysosome-dependent degradation of the protein. Finally, the loss of p27Kip1 ability in blocking cell proliferation was in part explained through the different binding efficiency that mutant p27Kip1 forms exhibited with Cyclin/Cyclin-dependent Kinase complexes (or proteins involved indirectly in that binding) with respect to the WT. Full article
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