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Cell Cycle (Georgetown, Tex.) Jan 2020The cell cycle is tightly regulated by cyclins and their catalytic moieties, the cyclin-dependent kinases (CDKs). Cyclin D1, in association with CDK4/6, acts as a... (Review)
Review
The cell cycle is tightly regulated by cyclins and their catalytic moieties, the cyclin-dependent kinases (CDKs). Cyclin D1, in association with CDK4/6, acts as a mitogenic sensor and integrates extracellular mitogenic signals and cell cycle progression. When deregulated (overexpressed, accumulated, inappropriately located), cyclin D1 becomes an oncogene and is recognized as a driver of solid tumors and hemopathies. Recent studies on the oncogenic roles of cyclin D1 reported non-canonical functions dependent on the partners of cyclin D1 and its location within tumor cells or tissues. Support for these new functions was provided by various mouse models of oncogenesis. Finally, proteomic and transcriptomic data identified complex cyclin D1 networks. This review focuses on these aspects of cyclin D1 pathophysiology, which may be crucial for targeted therapy. aa, amino acid; AR, androgen receptor; ATM, ataxia telangectasia mutant; ATR, ATM and Rad3-related; CDK, cyclin-dependent kinase; ChREBP, carbohydrate response element binding protein; CIP, CDK-interacting protein; CHK1/2, checkpoint kinase 1/2; CKI, CDK inhibitor; DDR, DNA damage response; DMP1, cyclin D-binding myb-like protein; DSB, double-strand DNA break; DNA-PK, DNA-dependent protein kinase; ER, estrogen receptor; FASN, fatty acid synthase; GSK3β, glycogen synthase-3β; HAT, histone acetyltransferase; HDAC, histone deacetylase; HK2, hexokinase 2; HNF4α, and hepatocyte nuclear factor 4α; HR, homologous recombination; IR, ionizing radiation; KIP, kinase inhibitory protein; MCL, mantle cell lymphoma; NHEJ, non-homologous end-joining; PCAF, p300/CREB binding-associated protein; PGC1α, PPARγ co-activator 1α; PEST, proline-glutamic acid-serine-threonine, PK, pyruvate kinase; PPAR, peroxisome proliferator-activated receptor; RB1, retinoblastoma protein; ROS, reactive oxygen species; SRC, steroid receptor coactivator; STAT, signal transducer and activator of transcription; TGFβ, transforming growth factor β; UPS, ubiquitin-proteasome system; USP22, ubiquitin-specific peptidase 22; XPO1 (or CRM1) exportin 1.
Topics: Animals; Carcinogenesis; Cell Nucleus; Cyclin D1; DNA Damage; Humans; Neoplasm Invasiveness; Neoplasms
PubMed: 31885322
DOI: 10.1080/15384101.2019.1706903 -
Cancer Cell Jun 2021Abnormal activity of the core cell-cycle machinery is seen in essentially all tumor types and represents a driving force of tumorigenesis. Recent studies revealed that... (Review)
Review
Abnormal activity of the core cell-cycle machinery is seen in essentially all tumor types and represents a driving force of tumorigenesis. Recent studies revealed that cell-cycle proteins regulate a wide range of cellular functions, in addition to promoting cell division. With the clinical success of CDK4/6 inhibitors, it is becoming increasingly clear that targeting individual cell-cycle components may represent an effective anti-cancer strategy. Here, we discuss the potential of inhibiting different cell-cycle proteins for cancer therapy.
Topics: Animals; Antineoplastic Agents; Cell Cycle; Cyclin D; Cyclin E; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Humans; Mice; Molecular Targeted Therapy; Neoplasms
PubMed: 33891890
DOI: 10.1016/j.ccell.2021.03.010 -
Nature Apr 2021Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free...
Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway. Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1-cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis.
Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Line; Cell Proliferation; Checkpoint Kinase 1; Cyclin D; Cyclin-Dependent Kinases; DNA Replication; Gene Expression Regulation, Developmental; Genes, Tumor Suppressor; Genomic Instability; Humans; Mice; Mice, Knockout; S Phase; Synthetic Lethal Mutations
PubMed: 33854232
DOI: 10.1038/s41586-021-03422-5 -
Nature Apr 2021The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclin D) couple these inputs to the initiation...
The initiation of cell division integrates a large number of intra- and extracellular inputs. D-type cyclins (hereafter, cyclin D) couple these inputs to the initiation of DNA replication. Increased levels of cyclin D promote cell division by activating cyclin-dependent kinases 4 and 6 (hereafter, CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma tumour suppressor. Accordingly, increased levels and activity of cyclin D-CDK4/6 complexes are strongly linked to unchecked cell proliferation and cancer. However, the mechanisms that regulate levels of cyclin D are incompletely understood. Here we show that autophagy and beclin 1 regulator 1 (AMBRA1) is the main regulator of the degradation of cyclin D. We identified AMBRA1 in a genome-wide screen to investigate the genetic basis of the response to CDK4/6 inhibition. Loss of AMBRA1 results in high levels of cyclin D in cells and in mice, which promotes proliferation and decreases sensitivity to CDK4/6 inhibition. Mechanistically, AMBRA1 mediates ubiquitylation and proteasomal degradation of cyclin D as a substrate receptor for the cullin 4 E3 ligase complex. Loss of AMBRA1 enhances the growth of lung adenocarcinoma in a mouse model, and low levels of AMBRA1 correlate with worse survival in patients with lung adenocarcinoma. Thus, AMBRA1 regulates cellular levels of cyclin D, and contributes to cancer development and the response of cancer cells to CDK4/6 inhibitors.
Topics: Adaptor Proteins, Signal Transducing; Adenocarcinoma of Lung; Animals; Cell Division; Cyclin D; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Genes, Tumor Suppressor; Humans; Lung Neoplasms; Mice; Piperazines; Pyridines; U937 Cells; Ubiquitination
PubMed: 33854239
DOI: 10.1038/s41586-021-03474-7 -
Journal of the American Chemical Society Dec 2022Proteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed for...
Proteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed for numerous protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins that do not have small-molecule binders. Here, we present a novel PROTAC approach, termed bridged PROTAC, which utilizes a small-molecule binder of the target protein's binding partner to recruit the protein complex into close proximity with an E3 ubiquitin ligase to target undruggable proteins. Applying this bridged PROTAC strategy, we discovered MS28, the first-in-class degrader of cyclin D1, which lacks a small-molecule binder. MS28 effectively degrades cyclin D1, with faster degradation kinetics and superior degradation efficiency than CDK4/6, through recruiting the CDK4/6-cyclin D1 complex to the von Hippel-Lindau E3 ligase. MS28 also suppressed the proliferation of cancer cells more effectively than CDK4/6 inhibitors and degraders. Altogether, the bridged PROTAC strategy could provide a generalizable platform for targeting undruggable proteins.
Topics: Proteolysis; Cyclin D1; Proteolysis Targeting Chimera; Ubiquitin-Protein Ligases; Proteins
PubMed: 36448571
DOI: 10.1021/jacs.2c09255 -
Signal Transduction and Targeted Therapy Jul 2023Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types...
Due to the essential role of cyclin D1 in regulating transition from G1 to S phase in cell cycle, aberrant cyclin D1 expression is a major oncogenic event in many types of cancers. In particular, the dysregulation of ubiquitination-dependent degradation of cyclin D1 contributes to not only the pathogenesis of malignancies but also the refractory to cancer treatment regiments with CDK4/6 inhibitors. Here we show that in colorectal and gastric cancer patients, MG53 is downregulated in more than 80% of tumors compared to the normal gastrointestinal tissues from the same patient, and the reduced MG53 expression is correlated with increased cyclin D1 abundance and inferior survival. Mechanistically, MG53 catalyzes the K48-linked ubiquitination and subsequent degradation of cyclin D1. Thus, increased expression of MG53 leads to cell cycle arrest at G1, and thereby markedly suppresses cancer cell proliferation in vitro as well as tumor growth in mice with xenograft tumors or AOM/DSS induced-colorectal cancer. Consistently, MG53 deficiency results in accumulation of cyclin D1 protein and accelerates cancer cell growth both in culture and in animal models. These findings define MG53 as a tumor suppressor via facilitating cyclin D1 degradation, highlighting the therapeutic potential of targeting MG53 in treating cancers with dysregulated cyclin D1 turnover.
Topics: Humans; Animals; Mice; Ubiquitin-Protein Ligases; Cyclin D1; Cell Proliferation; Cell Cycle Checkpoints; Stomach Neoplasms; Membrane Proteins
PubMed: 37414783
DOI: 10.1038/s41392-023-01458-9 -
Seminars in Cancer Biology Dec 2020D cyclins include three isoforms: D1, D2, and D3. D cyclins heterodimerize with cyclin-dependent kinase 4/6 (CDK4/6) to form kinase complexes that can phosphorylate and... (Review)
Review
D cyclins include three isoforms: D1, D2, and D3. D cyclins heterodimerize with cyclin-dependent kinase 4/6 (CDK4/6) to form kinase complexes that can phosphorylate and inactivate Rb. Inactivation of Rb triggers the activation of E2F transcription factors, which in turn regulate the expression of genes whose products drive cell cycle progression. Because D-type cyclins function as mitogenic sensors that link growth factor signaling directly with G phase progression, it is not surprising that D cyclin accumulation is dysregulated in a variety of human tumors. Elevated expression of D cyclins results from gene amplification, increased gene transcription and protein translation, decreased microRNA levels, and inefficiency or loss of ubiquitylation-mediated protein degradation. This review focuses on the clinicopathological importance of D cyclins, how dysregulation of Ubiquitin-Proteasome System (UPS) contributes to the overexpression of D cyclins, and the therapeutic potential through targeting D cyclin-related machinery in human tumors.
Topics: Cyclin D; Drug Resistance, Neoplasm; F-Box Proteins; Glutamine; Humans; Molecular Targeted Therapy; Neoplasms; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 32006569
DOI: 10.1016/j.semcancer.2020.01.012 -
Circulation Research Dec 2023Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular...
BACKGROUND
Pulmonary hypertension (PH) is a chronic vascular disease characterized, among other abnormalities, by hyperproliferative smooth muscle cells and a perturbed cellular redox and metabolic balance. Oxidants induce cell cycle arrest to halt proliferation; however, little is known about the redox-regulated effector proteins that mediate these processes. Here, we report a novel kinase-inhibitory disulfide bond in cyclin D-CDK4 (cyclin-dependent kinase 4) and investigate its role in cell proliferation and PH.
METHODS
Oxidative modifications of cyclin D-CDK4 were detected in human pulmonary arterial smooth muscle cells and human pulmonary arterial endothelial cells. Site-directed mutagenesis, tandem mass-spectrometry, cell-based experiments, in vitro kinase activity assays, in silico structural modeling, and a novel redox-dead constitutive knock-in mouse were utilized to investigate the nature and definitively establish the importance of CDK4 cysteine modification in pulmonary vascular cell proliferation. Furthermore, the cyclin D-CDK4 oxidation was assessed in vivo in the pulmonary arteries and isolated human pulmonary arterial smooth muscle cells of patients with pulmonary arterial hypertension and in 3 preclinical models of PH.
RESULTS
Cyclin D-CDK4 forms a reversible oxidant-induced heterodimeric disulfide dimer between C7/8 and C135, respectively, in cells in vitro and in pulmonary arteries in vivo to inhibit cyclin D-CDK4 kinase activity, decrease Rb (retinoblastoma) protein phosphorylation, and induce cell cycle arrest. Mutation of CDK4 C135 causes a kinase-impaired phenotype, which decreases cell proliferation rate and alleviates disease phenotype in an experimental mouse PH model, suggesting this cysteine is indispensable for cyclin D-CDK4 kinase activity. Pulmonary arteries and human pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension display a decreased level of CDK4 disulfide, consistent with CDK4 being hyperactive in human pulmonary arterial hypertension. Furthermore, auranofin treatment, which induces the cyclin D-CDK4 disulfide, attenuates disease severity in experimental PH models by mitigating pulmonary vascular remodeling.
CONCLUSIONS
A novel disulfide bond in cyclin D-CDK4 acts as a rapid switch to inhibit kinase activity and halt cell proliferation. This oxidative modification forms at a critical cysteine residue, which is unique to CDK4, offering the potential for the design of a selective covalent inhibitor predicted to be beneficial in PH.
Topics: Humans; Mice; Animals; Cyclins; Pulmonary Arterial Hypertension; Cysteine; Endothelial Cells; Cell Proliferation; Pulmonary Artery; Phosphorylation; Cell Cycle Checkpoints; Cyclin D; Cells, Cultured; Cyclin-Dependent Kinase 4
PubMed: 37955182
DOI: 10.1161/CIRCRESAHA.122.321836 -
Genes Jul 2023D-type cyclins encode G1/S cell cycle checkpoint proteins, which play a crucial role in defining cell cycle exit and progression. Precise control of cell cycle exit is... (Review)
Review
D-type cyclins encode G1/S cell cycle checkpoint proteins, which play a crucial role in defining cell cycle exit and progression. Precise control of cell cycle exit is vital during embryonic development, with defects in the pathways regulating intracellular D-type cyclins resulting in abnormal initiation of stem cell differentiation in a variety of different organ systems. Furthermore, stabilisation of D-type cyclins is observed in a wide range of disorders characterized by cellular over-proliferation, including cancers and overgrowth disorders. In this review, we will summarize and compare the roles played by each D-type cyclin during development and provide examples of how their intracellular dysregulation can be an underlying cause of disease.
Topics: Cyclins; Cyclin D3; Cell Division; Cell Cycle; Cell Proliferation
PubMed: 37510349
DOI: 10.3390/genes14071445 -
Cancer Treatment and Research... 2021Cyclins are key regulators of cell cycle progression and survival. Particularly cyclins D (cyclin D1, D2, and D3) act in response to the mitogenic stimulation and are... (Review)
Review
Cyclins are key regulators of cell cycle progression and survival. Particularly cyclins D (cyclin D1, D2, and D3) act in response to the mitogenic stimulation and are pivotal mediators between proliferative pathways and the nuclear cell cycle machinery. Dysregulation of cyclins expression results in impaired development, abnormal cell growth or tumorigenesis. In this review we summarize current knowledge about regulatory role of the cyclin D promoters, transcriptional factors: regulators, co-activators and adaptor proteins necessary to their activation. We focused on the intracellular signaling pathways vital to cell growth, differentiation and apoptosis including transcription factor families: activator protein 1 (AP1), nuclear factor (NFκB), signal transducer and activator of transcription (STAT), cAMP response element-binding protein (CREB) and Sp/NF-Y, with a special insight into the tissue specific cyclin representation.
Topics: Animals; Apoptosis; Carcinogenesis; Cell Differentiation; Cell Division; Cyclin D; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasms; Prognosis; Promoter Regions, Genetic; Signal Transduction; Transcription Factors
PubMed: 33618151
DOI: 10.1016/j.ctarc.2021.100338