Immunomodulatory Roles of Cell Cycle Regulators

Laphanuwat, Phatthamon; Jirawatnotai, Siwanon

doi:10.3389/fcell.2019.00023

Cited by 52 publications

(43 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although the literature of CDK2 in the context of innate immunity and inflammation is scarce (as reviewed in ref. 57), CDK2 possibly regulates the secretion of inflammatory cytokines in macrophages. In addition, a single-nucleotide polymorphism of CDK2 is significantly enriched in asthma patients (58), supporting the possible function of CDK2 in regulating inflammation.…”

Section: Discussionmentioning

confidence: 99%

Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration

Hsu

Wang

Liu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Neutrophil migration is essential for inflammatory responses to kill pathogens; however, excessive neutrophilic inflammation also leads to tissue injury and adverse effects. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA (miRNA) overexpression screen in zebrafish and identified 8 miRNAs as potent suppressors of neutrophil migration. Among those,miR-199decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils,miR-199alters the cell cycle-related pathways and directly suppresses cyclin-dependent kinase 2 (Cdk2), whose known activity is restricted to cell cycle progression and cell differentiation. Inhibiting Cdk2, but not DNA replication, disrupts cell polarity and chemotaxis of zebrafish neutrophils without inducing cell death. Human neutrophil-like cells deficient in CDK2 fail to polarize and display altered signaling downstream of the formyl peptide receptor. Chemotaxis of primary human neutrophils is also reduced upon CDK2 inhibition. Furthermore,miR-199overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Our results therefore reveal previously unknown functions ofmiR-199and CDK2 in regulating neutrophil migration and provide directions in alleviating systemic inflammation.

show abstract

Section: Discussionmentioning

confidence: 99%

Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration

Hsu

Wang

Liu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Another defined mechanisms by which L-arg starvation restricts T-cells activation and proliferation is the regulation of cell cycle progression (232) via modulation of cyclin D3 mRNA stability (240). Cyclins, including cyclin D3 (241), are critical regulators of the cell cycle, immune cells development and proliferation (242). L-arg starvation arrests human T-cells in G 0 -G 1 phase (232).…”

Section: Cell Cycle Arrestmentioning

confidence: 99%

Myeloid Cell-Derived Arginase in Cancer Immune Response

et al. 2020

View full text Add to dashboard Cite

Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

show abstract

“…CDK4/6 inhibitors could repress immunosuppressive regulatory T cells (Tregs) and enhance effector T cells response by upregulating the level of cytokines (IL-2) in the tumor microenvironment [94]. Cyclin D-CDK4 complex was also reported to play a role in reducing the expression of PD-L1; therefore CDK4/6 inhibitors could promote expression of PD-L1, causing tumor immune evasion [95,96]. These findings suggested that CDK4/6 inhibitors showed combinatorial benefit when combined with anti-PD-L1 therapy.…”

Section: Biological Rationale For Novel Combination Strategiesmentioning

confidence: 99%

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Piezzo

Cocco

Caputo

et al. 2020

IJMS

109

View full text Add to dashboard Cite

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

show abstract

Immunomodulatory Roles of Cell Cycle Regulators

Cited by 52 publications

References 40 publications

Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration

Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration

Myeloid Cell-Derived Arginase in Cancer Immune Response

Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Contact Info

Product

Resources

About