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

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 12, 2025

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

Language: Английский

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Unveiling the impact of CD133 on cell cycle regulation in radio- and chemo-resistance of cancer stem cells

Frontiers in Public Health, Journal Year: 2025, Volume and Issue: 13

Published: Feb. 6, 2025

The adaptation of malignancy to therapy presents a significant challenge in cancer treatment. cell cycle plays crucial role regulating the evolution radio- and chemo-resistance tumor cells. Cancer stem cells (CSCs) are primary source resistance, with CD133 being one most recognized valuable surface markers CSCs. Evidence increasingly suggests that is associated resistance. current understanding molecular biological function limited, leading ongoing debates about its biology. In this review, we explore recent research emerging trends related through extensive literature content analysis. It was summarized new insights into relationships signaling pathways resistant aim review provide foundational how these their interactions impact prognosis inform treatment strategies.

Language: Английский

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Cyclin‐dependent kinases: Masters of the eukaryotic universe

Wiley Interdisciplinary Reviews - RNA, Journal Year: 2023, Volume and Issue: 15(1)

Published: Sept. 17, 2023

Abstract A family of structurally related cyclin‐dependent protein kinases (CDKs) drives many aspects eukaryotic cell function. Much the literature in this area has considered individual members to act primarily either as regulators cycle, context which CDKs were first discovered, or transcription. Until recently, CDK7 was only clear example a CDK that functions both processes. However, new data points several “cell‐cycle” having important roles transcription and some “transcriptional” cycle‐related targets. For example, novel have been demonstrated for archetypal cycle regulator CDK1. The increasing evidence overlap between these two types suggests they might play critical role coordinating Here we review canonical cell‐cycle transcriptional CDKs, provide an update on how collaborate perform cellular functions. We also brief overview dysregulation contributes carcinogenesis, possible treatment avenues. This article is categorized under: RNA Interactions with Proteins Other Molecules > RNA‐Protein Complexes Processing 3′ End Splicing Regulation/Alternative

Language: Английский

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CDK14 regulates the development and repair of lung

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Jan. 18, 2025

Cyclin-dependent kinases (CDK) 14 regulates cell cycle, tumor expansion by influencing the downstream targets of canonical Wnt signaling pathway. However, function CDK14 during organ development and regeneration has not been investigated in genetically-modified animals. Here, we found that genetic ablation Cdk14 influenced pulmonary vascular endothelial cells alveolar epithelial mice embryonic as well repair lung after bleomycin or lipopolysaccharide induced injury. Genetic knockout covalent inhibitor FMF-04-159-2 resulted reduction vessel covered area number, exhibiting increased mortality more severe damage Mechanistically, inhibited proliferation cells, inducing cycle arrest at G2/M phase. Through RNA-seq analysis both knockdown controls expression signal transducers activator transcription 1 (STAT1) associated genes interferon signaling. Disruption interferes with IFN-γ vivo, suggesting potential crosstalk Our work highlights importance regenerative through an uncharacterized CDK14- axis.

Language: Английский

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Binding Mechanism of Inhibitors to CDK6 Deciphered by Multiple Independent Molecular Dynamics Simulations and Free Energy Predictions

Molecules, Journal Year: 2025, Volume and Issue: 30(5), P. 979 - 979

Published: Feb. 20, 2025

Cyclin-dependent kinase 6 (CDK6) has been identified as a potential drug target in various types of cancers. In our current study, multiple independent molecular dynamics simulations four separate replicates and computations binding free energies are carried out to decipher the mechanisms three inhibitors, LQQ, 6ZV, 0RS, CDK6. The dynamic analyses indicate that presence inhibitors influences conformational alterations, motion modes, internal Binding computed using mechanics generalized Born surface area (MM-GBSA) approach with GB models demonstrate hydrophobic interactions play essential roles inhibitor-CDK6 binding. residue-based energy decomposition verify side chains residues I19, K29, M54, P55, F98, H100, L152 significantly contribute binding, revealing critical interaction sites for information revealed study can provide theoretical aids development potent targeting CDK family.

Language: Английский

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Untangling the Role of MYC in Sarcomas and Its Potential as a Promising Therapeutic Target

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 1973 - 1973

Published: Feb. 25, 2025

MYC plays a pivotal role in the biology of various sarcoma subtypes, acting as key regulator tumor growth, proliferation, and metabolic reprogramming. This oncogene is frequently dysregulated across different sarcomas, where its expression closely intertwined with molecular features unique to each subtype. interacts critical pathways such cell cycle regulation, apoptosis, angiogenesis, amplifying aggressiveness resistance standard therapies. Furthermore, influences microenvironment by modulating cell-extracellular matrix interactions immune evasion mechanisms, further complicating therapeutic management. Despite well-established centrality pathogenesis, targeting directly remains challenging due "undruggable" protein structure. However, emerging strategies, including indirect inhibition via epigenetic modulators, transcriptional machinery disruptors, pathway inhibitors, offer new hope for treatment. review underscores importance understanding intricate roles subtypes guide development effective targeted Given MYC's central tumorigenesis progression, innovative approaches aiming at could transform landscape patients, providing much-needed avenue overcome improve clinical outcomes.

Language: Английский

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PAF1C-mediated activation of CDK12/13 kinase activity is critical for CTD phosphorylation and transcript elongation

Molecular Cell, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

The transcription cycle is regulated by dynamic changes in RNA polymerase II (RNAPII) C-terminal domain (CTD) phosphorylation, which are crucial for gene expression. However, the mechanisms regulating transcription-specific cyclin-dependent kinases (CDKs) during remain poorly understood. Here, we show that human CDK12 co-phosphorylates CTD Serine2 and Serine5. This di-phosphorylated Serine2-Serine5 mark may then act as a precursor mono-phosphorylated through Serine5 de-phosphorylation. Notably, specifically association with elongation-specific factor PAF1 complex (PAF1C), CDC73 subunit contains metazoan-specific peptide motif, capable of allosteric CDK12/cyclin K activation. motif essential cell proliferation required normal levels phosphorylation chromatin, transcript elongation, particularly across long genes. Together, these findings provide insight into governing RNAPII phospho-CTD dynamics ensure progression cycle.

Language: Английский

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The Molecular Basis of Pediatric Brain Tumors: A Review with Clinical Implications

Cancers, Journal Year: 2025, Volume and Issue: 17(9), P. 1566 - 1566

Published: May 4, 2025

Central nervous system (CNS) tumors are the most common solid malignancy in pediatric population. These lesions result of aberrant cell signaling step proteins, which normally regulate proliferation. Mitogen-activated protein kinase (MAPK) pathways and tyrosine receptors involved tumorigenesis low-grade gliomas. High-grade gliomas may carry similar mutations, but loss epigenetic control is dominant molecular event; it can occur either due to histone mutations or inappropriate binding unbinding DNA on histones. Therefore, despite absence genetic alteration classic oncogenes tumor suppressor genes, uncontrolled transcription results tumorigenesis. Isocitric dehydrogenase (IDH) do not predominate compared their adult counterpart. Embryonic include medulloblastomas, bear transcription-regulating pathways, such as wingless-related integration sites sonic hedgehog pathways. They also relate high expression Myc family genes. Atypical teratoid rhabdoid harbor alterations molecules that contribute ATP hydrolysis chromatin. with multilayered rosettes associated microRNA impaired translation. Ependymomas exhibit great variability. As far supratentorial concerned, major events NFkB Hippo Posterior fossa further divided into two types different prognoses. Type A group damage repair molecules. Lastly, germ a heterogeneous group. Among them, germinomas manifest KIT receptor subgroup family.

Language: Английский

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Structure-Guided Discovery of Novel N⁴-(Substituted Thiazol-2-yl)-N²-(4-Substituted phenyl)pyrimidine-2,4-Diamines as Potent CDK2 and CDK9 Dual Inhibitors with High Oral Bioavailability

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

CDK2 and CDK9 play pivotal roles in cell cycle progression gene transcription, respectively, making them promising targets for cancer treatment. Herein, we discovered a series of N4-(substituted thiazol-2-yl)-N2-(4-substituted phenyl)pyrimidine-2,4-diamines as highly potent CDK2/9 dual inhibitors. Especially, compound 20a significantly inhibited (IC50 = 0.004 μM) 0.009 μM), achieving 1000- 2800-fold improvement over lead 11, demonstrating broad antitumor efficacy. Mechanistic studies indicated that effectively simultaneously suppressed proteins the HCT116 line, leading to G2/M arrest apoptosis by regulating cycle- apoptosis-related protein expression. Most importantly, exhibited 86.7% oral bioavailability rats tumor growth xenograft C6 glioma rat models without significant toxicity. Overall, these observations clearly confirmed therapeutic strategy inhibitors provided novel candidate therapy.

Language: Английский

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The involvement of cyclin-dependent kinase 7 (CDK7) and 9 (CDK9) in coordinating transcription and cell cycle checkpoint regulation

Cell Cycle, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13

Published: April 14, 2025

Cells regulate the expression of cell cycle-related genes, including cyclins essential for mitosis, through transcriptional activity positive transcription elongation factor b (P-TEFb), a complex comprising CDK9, cyclin T, and factors. P-TEFb cooperates with CDK7 to activate RNA polymerase. In response DNA stress, cycle shifts from mitosis repair, triggering arrest activation repair genes. This tight coordination between transcription, progression, stress is crucial maintaining cellular integrity. Cyclin-dependent kinases CDK9 are central both regulation. functions as CDK-activating kinase (CAK), activating other CDKs, while acts critical integrator signals machinery. review elucidates mechanisms by which mitotic process checkpoints, emphasizing their roles in balancing growth, homeostasis, control.

Language: Английский

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