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Cell Cycle Control and Cancer

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Proliferation and Division".

Deadline for manuscript submissions: closed (1 November 2020) | Viewed by 71465

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Dr. Libor Macurek

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Department of Cancer Cell Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
Interests: cell cycle; checkpoint; protein phosphorylation; oncogenic transformation

Special Issue Information

Dear Colleagues,

Duplication of the genome followed by cell division is essential for keeping tissue homoeostasis in multicellular organisms. Progression through the cell cycle is tightly regulated by evolutionary conserved cyclin-dependent kinases. In the presence of DNA damage, cells temporarily arrest in the checkpoints to allow DNA repair or they are permanently eliminated by senescence or apoptosis. Replication stress caused by activation of oncogenes is emerging as a major source of DNA damage in precancerous lesions, whereas the checkpoint arrest and apoptosis are now recognized as an intrinsic barrier preventing development of genome instability and cell transformation. Genetic defects in the core cell cycle regulators as well as in DNA repair and surveillance mechanisms are common in human cancers. Most typically, loss of the tumor suppressor p53 allows cell proliferation in the presence of genotoxic stress and promotes genome instability. At the same time, deficient cell cycle control may cause increased vulnerability of cancer cells to various treatments. Inhibitors of the checkpoint kinases CHK1 and WEE1 in combination with various DNA damaging agents efficiently eliminate p53-deficient cancer cells and are now being clinically tested in cancer therapy. Alternative approaches target the negative regulators of p53 (including MDM2 and WIP1) or the mutant p53 itself to allow reactivation of the p53 function, leading to cytotoxicity in cancer cells. Finally, specific CDK4/6 inhibitors significantly improve progression free survival in advanced ER+ breast cancer patients and are now being tested in other clinical settings. Despite the promising results in preclinical testing of the cell cycle targeting drugs, resistance commonly develops during the cancer treatment. Therefore, better understanding of the general molecular mechanisms, identification of new synthetically lethal combinations of the drugs or genetic defects as well as identification of suitable biomarkers are critically needed for exploitation of the cell cycle inhibitors in cancer therapy.

This Special Issue will cover all areas of the cell cycle and checkpoint control in normal and cancer cells. Both original research articles and reviews are welcome.

Dr. Libor Macurek
Guest Editor

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Keywords

cell cycle
checkpoint
senescence
DNA damage
replication stress
P53 pathway
synthetic lethality
CHK1 and WEE1 inhibitors
CDK4 inhibitor

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Published Papers (12 papers)

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Research

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16 pages, 2909 KiB

Open AccessArticle

Combined Inactivation of Pocket Proteins and APC/C^Cdh1 by Cdk4/6 Controls Recovery from DNA Damage in G1 Phase

by Indra A. Shaltiel, Alba Llopis, Melinda Aprelia, Rob Klompmaker, Apostolos Menegakis, Lenno Krenning and René H. Medema

Cells 2021, 10(3), 550; https://doi.org/10.3390/cells10030550 - 4 Mar 2021

Viewed by 2515

Abstract

Most Cyclin-dependent kinases (Cdks) are redundant for normal cell division. Here we tested whether these redundancies are maintained during cell cycle recovery after a DNA damage-induced arrest in G1. Using non-transformed RPE-1 cells, we find that while Cdk4 and Cdk6 act redundantly during normal S-phase entry, they both become essential for S-phase entry after DNA damage in G1. We show that this is due to a greater overall dependency for Cdk4/6 activity, rather than to independent functions of either kinase. In addition, we show that inactivation of pocket proteins is sufficient to overcome the inhibitory effects of complete Cdk4/6 inhibition in otherwise unperturbed cells, but that this cannot revert the effects of Cdk4/6 inhibition in DNA damaged cultures. Indeed, we could confirm that, in addition to inactivation of pocket proteins, Cdh1-dependent anaphase-promoting complex/cyclosome (APC/C^Cdh1) activity needs to be inhibited to promote S-phase entry in damaged cultures. Collectively, our data indicate that DNA damage in G1 creates a unique situation where high levels of Cdk4/6 activity are required to inactivate pocket proteins and APC/C^Cdh1 to promote the transition from G1 to S phase. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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19 pages, 3232 KiB

Open AccessArticle

Photochemotherapy Induces Interferon Type III Expression via STING Pathway

by Edyta Biskup, Brian Daniel Larsen, Leonor Rib, Lasse Folkersen, Omid Niazi, Maria R. Kamstrup and Claus Storgaard Sørensen

Cells 2020, 9(11), 2452; https://doi.org/10.3390/cells9112452 - 10 Nov 2020

Cited by 2 | Viewed by 3438

Abstract

DNA-damaging cancer therapies induce interferon expression and stimulate the immune system, promoting therapy responses. The immune-activating STING (Stimulator of Interferon Genes) pathway is induced when DNA or double-stranded RNA (dsRNA) is detected in the cell cytoplasm, which can be caused by viral infection or by DNA damage following chemo- or radiotherapy. Here, we investigated the responses of cutaneous T-cell lymphoma (CTCL) cells to the clinically applied DNA crosslinking photochemotherapy (combination of 8–methoxypsoralen and UVA light; 8–MOP + UVA). We showed that this treatment evokes interferon expression and that the type III interferon IFNL1 is the major cytokine induced. IFNL1 upregulation is dependent on STING and on the cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS). Furthermore, 8–MOP + UVA treatment induced the expression of genes in pathways involved in response to the tumor necrosis factor, innate immune system and acute inflammatory response. Notably, a subset of these genes was under control of the STING–IFNL1 pathway. In conclusion, our data connected DNA damage with immune system activation via the STING pathway and contributed to a better understanding of the effectiveness of photochemotherapy. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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14 pages, 2211 KiB

Open AccessArticle

FRET-Based Sorting of Live Cells Reveals Shifted Balance between PLK1 and CDK1 Activities During Checkpoint Recovery

by Lorenzo Lafranchi, Erik Müllers, Dorothea Rutishauser and Arne Lindqvist

Cells 2020, 9(9), 2126; https://doi.org/10.3390/cells9092126 - 19 Sep 2020

Cited by 3 | Viewed by 4154

Abstract

Cells recovering from the G2/M DNA damage checkpoint rely more on Aurora A-PLK1 signaling than cells progressing through an unperturbed G2 phase, but the reason for this discrepancy is not known. Here, we devised a method based on a FRET reporter for PLK1 activity to sort cells in distinct populations within G2 phase. We employed mass spectroscopy to characterize changes in protein levels through an unperturbed G2 phase and validated that ATAD2 levels decrease in a proteasome-dependent manner. Comparing unperturbed cells with cells recovering from DNA damage, we note that at similar PLK1 activities, recovering cells contain higher levels of Cyclin B1 and increased phosphorylation of CDK1 targets. The increased Cyclin B1 levels are due to continuous Cyclin B1 production during a DNA damage response and are sustained until mitosis. Whereas partial inhibition of PLK1 suppresses mitotic entry more efficiently when cells recover from a checkpoint, partial inhibition of CDK1 suppresses mitotic entry more efficiently in unperturbed cells. Our findings provide a resource for proteome changes during G2 phase, show that the mitotic entry network is rewired during a DNA damage response, and suggest that the bottleneck for mitotic entry shifts from CDK1 to PLK1 after DNA damage. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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15 pages, 2747 KiB

Open AccessArticle

Truncated PPM1D Prevents Apoptosis in the Murine Thymus and Promotes Ionizing Radiation-Induced Lymphoma

by Andra S. Martinikova, Monika Burocziova, Miroslav Stoyanov and Libor Macurek

Cells 2020, 9(9), 2068; https://doi.org/10.3390/cells9092068 - 10 Sep 2020

Cited by 4 | Viewed by 3692

Abstract

Genome integrity is protected by the cell-cycle checkpoints that prevent cell proliferation in the presence of DNA damage and allow time for DNA repair. The transient checkpoint arrest together with cellular senescence represent an intrinsic barrier to tumorigenesis. Tumor suppressor p53 is an integral part of the checkpoints and its inactivating mutations promote cancer growth. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of p53. Although its loss impairs recovery from the G2 checkpoint and promotes induction of senescence, amplification of the PPM1D locus or gain-of-function truncating mutations of PPM1D occur in various cancers. Here we used a transgenic mouse model carrying a truncating mutation in exon 6 of PPM1D (Ppm1d^T). As with human cell lines, we found that the truncated PPM1D was present at high levels in the mouse thymus. Truncated PPM1D did not affect differentiation of T-cells in the thymus but it impaired their response to ionizing radiation (IR). Thymocytes in Ppm1d^T/+ mice did not arrest in the checkpoint and continued to proliferate despite the presence of DNA damage. In addition, we observed a decreased level of apoptosis in the thymi of Ppm1d^T/+ mice. Moreover, the frequency of the IR-induced T-cell lymphomas increased in Ppm1d^T/+Trp53^+/− mice resulting in decreased survival. We conclude that truncated PPM1D partially suppresses the p53 pathway in the mouse thymus and potentiates tumor formation under the condition of a partial loss of p53 function. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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19 pages, 6311 KiB

Open AccessArticle

The E2F Pathway Score as a Predictive Biomarker of Response to Neoadjuvant Therapy in ER+/HER2− Breast Cancer

by Masanori Oshi, Hideo Takahashi, Yoshihisa Tokumaru, Li Yan, Omar M. Rashid, Masayuki Nagahashi, Ryusei Matsuyama, Itaru Endo and Kazuaki Takabe

Cells 2020, 9(7), 1643; https://doi.org/10.3390/cells9071643 - 8 Jul 2020

Cited by 83 | Viewed by 5087

Abstract

E2F transcription factors play critical roles in the cell cycle. Therefore, their activity is expected to reflect tumor aggressiveness and responsiveness to therapy. We scored 3905 tumors of nine breast cancer cohorts for this activity based on their gene expression for the Hallmark E2F targets gene set. As expected, tumors with a high score had an increased expression of cell proliferation-related genes. A high score was significantly associated with shorter patient survival, greater MKI67 expression, histological grade, stage, and genomic aberrations. Furthermore, metastatic tumors had higher E2F scores than the primary tumors from which they arose. Although tumors with a high score had greater infiltration by both pro- and anti-cancerous immune cells, they had an increased expression of immune checkpoint genes. Estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative cancer with a high E2F score achieved a significantly higher pathological complete response (pCR) rate to neoadjuvant chemotherapy. The E2F score was significantly associated with the expression of cyclin-dependent kinase (CDK)-related genes and strongly correlated with sensitivity to CDK inhibition in cell lines. In conclusion, the E2F score is a marker of breast cancer aggressiveness and predicts the responsiveness of ER-positive/HER2-negative patients to neoadjuvant chemotherapy and possibly to CDK and immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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15 pages, 1747 KiB

Open AccessArticle

Multiple Functions of Fubp1 in Cell Cycle Progression and Cell Survival

by Mingyu Kang, Hyeon Ji Kim, Tae-Jun Kim, Jin-Seok Byun, Jae-Ho Lee, Deok Heon Lee, Wanil Kim and Do-Yeon Kim

Cells 2020, 9(6), 1347; https://doi.org/10.3390/cells9061347 - 28 May 2020

Cited by 9 | Viewed by 3999

Abstract

The discovery of novel and critical genes implicated in malignant development is a topic of high interest in cancer research. Intriguingly, a group of genes named “double-agent” genes were reported to have both oncogenic and tumor-suppressive functions. To date, less than 100 “double-agent” genes have been documented. Fubp1 is a master transcriptional regulator of a subset of genes by interacting with a far upstream element (FUSE). Mounting evidence has collectively demonstrated both the oncogenic and tumor suppressive roles of Fubp1 and the debate regarding its roles in tumorigenesis has been around for several years. Therefore, the detailed molecular mechanisms of Fubp1 need to be determined in each context. In the present study, we showed that the Fubp1 protein level was enriched in the S phase and we identified that Fubp1 deficiency altered cell cycle progression, especially in the S phase, by downregulating the mRNA expression levels of Ccna genes encoding cyclin A. Although this Fubp1-cyclin A axis appears to exist in several types of tumors, Fubp1 showed heterogeneous expression patterns among various cancer tissues, suggesting it exhibits multiple and complicated functions in cancer development. In addition, we showed that Fubp1 deficiency confers survival advantages to cells against metabolic stress and anti-cancer drugs, suggesting that Fubp1 may play both positive and negative roles in malignant development. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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19 pages, 3493 KiB

Open AccessArticle

An Alternative Splice Variant of HIPK2 with Intron Retention Contributes to Cytokinesis

by Veronica Gatti, Manuela Ferrara, Ilaria Virdia, Silvia Matteoni, Laura Monteonofrio, Simona di Martino, Maria Grazia Diodoro, Giuliana Di Rocco, Cinzia Rinaldo and Silvia Soddu

Cells 2020, 9(2), 484; https://doi.org/10.3390/cells9020484 - 20 Feb 2020

Cited by 9 | Viewed by 3451

Abstract

HIPK2 is a DYRK-like kinase involved in cellular stress response pathways, development, and cell division. Two alternative splice variants of HIPK2, HIPK2-FL and HIPK2-Δe8, have been previously identified as having different protein stability but similar functional activity in the stress response. Here, we describe one additional HIPK2 splice variant with a distinct subcellular distribution and functional activity in cytokinesis. This novel splice variant lacks the last two exons and retains intron13 with a stop codon after 89 bp of the intron, generating a short isoform, HIPK2-S, that is detectable by 2D Western blots. RT-PCR analyses of tissue arrays and tumor samples show that HIPK2-FL and HIPK2-S are expressed in normal human tissues in a tissue-dependent manner and differentially expressed in human colorectal and pancreatic cancers. Gain- and loss-of-function experiments showed that in contrast to HIPK2-FL, HIPK2-S has a diffuse, non-speckled distribution and is not involved in the DNA damage response. Rather, we found that HIPK2-S, but not HIPK2-FL, localizes at the intercellular bridge, where it phosphorylates histone H2B and spastin, both required for faithful cell division. Altogether, these data show that distinct human HIPK2 splice variants are involved in distinct HIPK2-regulated functions like stress response and cytokinesis. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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Review

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16 pages, 729 KiB

Open AccessReview

Understanding How Genetic Mutations Collaborate with Genomic Instability in Cancer

by Laura J. Jilderda, Lin Zhou and Floris Foijer

Cells 2021, 10(2), 342; https://doi.org/10.3390/cells10020342 - 6 Feb 2021

Cited by 4 | Viewed by 3780

Abstract

Chromosomal instability is the process of mis-segregation for ongoing chromosomes, which leads to cells with an abnormal number of chromosomes, also known as an aneuploid state. Induced aneuploidy is detrimental during development and in primary cells but aneuploidy is also a hallmark of cancer cells. It is therefore believed that premalignant cells need to overcome aneuploidy-imposed stresses to become tumorigenic. Over the past decade, some aneuploidy-tolerating pathways have been identified through small-scale screens, which suggest that aneuploidy tolerance pathways can potentially be therapeutically exploited. However, to better understand the processes that lead to aneuploidy tolerance in cancer cells, large-scale and unbiased genetic screens are needed, both in euploid and aneuploid cancer models. In this review, we describe some of the currently known aneuploidy-tolerating hits, how large-scale genome-wide screens can broaden our knowledge on aneuploidy specific cancer driver genes, and how we can exploit the outcomes of these screens to improve future cancer therapy. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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43 pages, 1320 KiB

Open AccessReview

CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate

by Lenka Stolarova, Petra Kleiblova, Marketa Janatova, Jana Soukupova, Petra Zemankova, Libor Macurek and Zdenek Kleibl

Cells 2020, 9(12), 2675; https://doi.org/10.3390/cells9122675 - 12 Dec 2020

Cited by 112 | Viewed by 12907

Abstract

Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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15 pages, 1275 KiB

Open AccessReview

Cyclin D1 in Cancer: A Molecular Connection for Cell Cycle Control, Adhesion and Invasion in Tumor and Stroma

by Francesca Ida Montalto and Francesca De Amicis

Cells 2020, 9(12), 2648; https://doi.org/10.3390/cells9122648 - 9 Dec 2020

Cited by 255 | Viewed by 13576

Abstract

Cyclin D1, an important regulator of cell cycle, carries out a central role in the pathogenesis of cancer determining uncontrolled cellular proliferation. In normal cells, Cyclin D1 expression levels are strictly regulated, conversely, in cancer, its activity is intensified in various manners. Different studies demonstrate that CCDN1 gene is amplified in several tumor types considering it as a negative prognostic marker of this pathology. Cyclin D1 is known for its role in the nucleus, but recent clinical studies associate the amount located in the cytoplasmic membrane with tumor invasion and metastasis. Cyclin D1 has also other functions: it governs the expression of specific miRNAs and it plays a crucial role in the tumor-stroma interactions potentiating most of the cancer hallmarks. In the present review, we will summarize the current scientific evidences that highlight the involvement of Cyclin D1 in the pathogenesis of different types of cancer, best of all in breast cancer. We will also focus on recent insights regarding the Cyclin D1 as molecular bridge between cell cycle control, adhesion, invasion, and tumor/stroma/immune-system interplay in cancer. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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15 pages, 1800 KiB

Open AccessReview

Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma

by Paul J. Bröckelmann, Mathilde R. W. de Jong and Ron D. Jachimowicz

Cells 2020, 9(10), 2287; https://doi.org/10.3390/cells9102287 - 14 Oct 2020

Cited by 17 | Viewed by 5466

Abstract

The DNA double-strand break (DSB) is the most cytotoxic lesion and compromises genome stability. In an attempt to efficiently repair DSBs, cells activate ATM kinase, which orchestrates the DNA damage response (DDR) by activating cell cycle checkpoints and initiating DSB repair pathways. In physiological B cell development, however, programmed DSBs are generated as intermediates for effective immune responses and the maintenance of genomic integrity. Disturbances of these pathways are at the heart of B cell lymphomagenesis. Here, we review the role of DNA repair and cell cycle control on B cell development and lymphomagenesis. In addition, we highlight the intricate relationship between the DDR and the tumor microenvironment (TME). Lastly, we provide a clinical perspective by highlighting treatment possibilities of defective DDR signaling and the TME in mantle cell lymphoma, which serves as a blueprint for B cell lymphomas. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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15 pages, 1833 KiB

Open AccessReview

The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer

by Marina Andrade-Tomaz, Izadora de Souza, Clarissa Ribeiro Reily Rocha and Luciana Rodrigues Gomes

Cells 2020, 9(9), 2140; https://doi.org/10.3390/cells9092140 - 22 Sep 2020

Cited by 68 | Viewed by 7563

Abstract

The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autophagy, the catabolic pathway involved in degradation of intracellular constituents in lysosomes. According to the mechanism used to deliver cargo to the lysosome, autophagy can be classified as macroautophagy (MA), microautophagy (MI), or chaperone-mediated autophagy (CMA). Distinct from other autophagy types, CMA substrates are selectively recognized by a cytosolic chaperone, one-by-one, and then addressed for degradation in lysosomes. The function of MA in cell cycle control, and its influence in cancer progression, are already well-established. However, regulation of the cell cycle by CMA, in the context of tumorigenesis, has not been fully addressed. This review aims to present and debate the molecular mechanisms by which CMA can interfere in the cell cycle, in the context of cancer. Thus, cell cycle modulators, such as MYC, hypoxia-inducible factor-1 subunit alpha (HIF-1α), and checkpoint kinase 1 (CHK1), regulated by CMA activity will be discussed. Finally, the review will focus on how CMA dysfunction may impact the cell cycle, and as consequence promote tumorigenesis. Full article

(This article belongs to the Special Issue Cell Cycle Control and Cancer)

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