Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

Sante, Gabriele Di; Page, J Le; Jiao, Xuanmao; Nawab, Omar; Cristofanilli, Massimo; Skordalakes, Emmanuel; Pestell, Richard G.

doi:10.1080/14737140.2019.1615889

Cited by 21 publications

(21 citation statements)

References 216 publications

(271 reference statements)

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“…The signal for Akt1 and cyclin D1 proximity was maintained with a mutant of cyclin D1 (cyclin D1 KE ), which is defective in several functions, including kinase activity ( Figure 3C ). A mutant of a carboxy-terminal cyclin D1 phosphorylation site (cyclin D1 T286 ) that is known to be primarily nuclear in localization ( Di Sante et al, 2019 ; Alt et al, 2000 ) did not show association with Akt1 ( Figure 3D ; Figure S8 ). Deletion of the acidic rich carboxy-terminal motif from cyclin D1 (cyclin ΔE ) maintained binding to Akt1; however, deletion of the N-terminal residues 1–91 (cyclin D1 C6 ) abrogated Akt1 binding ( Figure 3E – 3G ), and mutants including deletions of this region (e.g., cyclin D1 C4 and cyclin D1 C5 ) also failed to bind Akt1 ( Figure S8 ).…”

Section: Resultsmentioning

confidence: 99%

“…Fluorescence-activated cell sorting (FACS) analysis demonstrated trivial differences in cell-cycle distribution in the 0- to 4-h time frame, with an augmentation of S phase enrichment (9.9 versus 13.5) occurring at 24 h ( Figure S9A ). CDK inhibitors have been shown to reduce the RB kinase function of the cyclin D1/CDK4 complex; however, significant additional interactions have been identified (reviewed in Di Sante et al, 2019 ), warranting an analysis of CDK inhibitor impact on Akt1 phosphorylation at Ser473 and the interaction with Rictor. To this end, we deployed MEFs encoding tamoxifen-inducible Rictor small interfering RNA (siRNA) ( Cybulski et al, 2012 ).…”

Section: Resultsmentioning

confidence: 99%

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Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation

et al. 2020

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SUMMARY Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates RB and functions as a collaborative nuclear oncogene. The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, and mitogenic signaling. Herein, Akt1-mediated phosphorylation of downstream substrates in the mammary gland is reduced by cyclin D1 genetic deletion and is induced by mammary-gland-targeted cyclin D1 overexpression. Cyclin D1 is associated with Akt1 and augments the rate of onset and maximal cellular Akt1 activity induced by mitogens. Cyclin D1 is identified in a cytoplasmic-membrane-associated pool, and cytoplasmic-membrane-localized cyclin D1—but not nuclear-localized cyclin D1—recapitulates Akt1 transcriptional function. These studies identify a novel extranuclear function of cyclin D1 to enhance proliferative functions via augmenting Akt1 phosphorylation at Ser473.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation

et al. 2020

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“…Firstly, the ethyl acetate fraction of the 95% ethanol extract of O. japonica selectively inhibited cyclin D1 and CDK4 expression, blocking entry into the G1 phase in A549, MDA-MB-231, A375, and PANC-1 cancer cells. Cyclin D1 plays a critical role as an oncogene; in particular, an increase in CDK4-cyclin D1 complex levels is an indicator of mammary carcinogenesis [ 50 ]. In this regard, it is possible to speculate that O. japonica might have preventive potential and offer better therapeutic effects against breast cancer, such as MDA-MB-231, via the suppression of protein expression in the early cell cycle.…”

Section: Anticancer Properties Of O Japonicamentioning

confidence: 99%

Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways

2021

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Tumors are one of the most life-threatening diseases, and a variety of cancer treatment options have been continuously introduced in order to overcome cancer and improve conventional therapy. Orostachys japonica (O. japonica), which is a perennial plant belonging to the genus Orostachys of the Crassulaceae family, has been revealed to exhibit pharmacological properties against various tumors in numerous studies. The present review aimed to discuss the biological actions and underlying molecular mechanisms of O. japonica and its representative compounds—kaempferol and quercetin—against tumors. O. japonica reportedly has antiproliferative, anti-angiogenic, and antimetastatic activities against various types of malignant tumors through the induction of apoptosis and cell cycle arrest, a blockade of downstream vascular endothelial growth factor (VEGF)-VEGFR2 pathways, and the regulation of epithelial-to-mesenchymal transition. In addition, emerging studies have highlighted the antitumor efficacy of kaempferol and quercetin. Interestingly, it was found that alterations of the mitogen-activated protein kinase (MAPK) signaling cascades are involved in the pivotal mechanisms of the antitumor effects of O. japonica and its two compounds against cancer cell overgrowth, angiogenesis, and metastasis. In summary, O. japonica could be considered a preventive and therapeutic medicinal plant which exhibits antitumor actions by reversing altered patterns of MAPK cascades, and kaempferol and quercetin might be potential components that can contribute to the efficacy and underlying mechanism of O. japonica.

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“…Cyclin-dependent kinase inhibitors (CKIs) bind CDKs and inhibit their activity to regulate the progression of the cell cycle. Consequently, CKI misregulation is associated with a multitude of diseases [136][137][138][139]. CKIs are IDPs that only share a conserved inhibitory domain (CID), which acquires a folded state when involved in cooperative binding to both CDKs and cyclins [140][141][142][143].…”

Section: Disordered Proteins Represent Key Regulators In Cell Cycle Pmentioning

confidence: 99%

Common Functions of Disordered Proteins across Evolutionary Distant Organisms

Wallmann

Kesten

2020

IJMS

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Intrinsically disordered proteins and regions typically lack a well-defined structure and thus fall outside the scope of the classic sequence-structure-function relationship. Hence, classic sequence-or structure-based bioinformatic approaches are often not well suited to identify homology or predict the function of unknown intrinsically disordered proteins. Here, we give selected examples of intrinsic disorder in plant proteins and present how protein function is shared, altered or distinct in evolutionary distant organisms. Furthermore, we explore how examining the specific role of disorder across different phyla can provide a better understanding of the common features that protein disorder contributes to the respective biological mechanism. being defined by a separate set of parameters compared to their structured and globular counterparts [7]. Hence, identification of distantly related IDPs cannot rely on structure, which can help to detect relationships of folded proteins that would remain undetected by conventional sequence-based methods [8]. Methods that use antibodies to metazoan proteins to identify putative plant homologues may result in a higher incidence of artefacts when compared to folded protein targets, due to the smaller size of disordered epitopes and their comparably higher sensitivity to epitope variation [9].In contrast to folded proteins, IDPs and IDRs show an overall increased rate of evolution, while these rates can strongly vary between different parts of the IDP [10,11]. Moreover, disordered regions appear to be more permissive to mutation, further complicating sequence-function analysis. Overall, genome duplication events seem to influence the distribution of IDRs within genomes, as the amount of identical paralogous IDRs positively correlates with the number of chromosomes [12]. Interestingly, proteins can display different modes of how sequence conservation can relate to disorder as a functional feature [13]. While in some cases only the disorder itself is conserved, but not the sequence facilitating it (flexible disorder), other IDPs retain disorder together with a highly conserved sequence (constrained disorder). Short-linear motifs (SLiMs) represent conserved functional modules that can mediate low-affinity interactions and are often interspersed by regions of flexible disorder [14]. As many alignment algorithms require long stretches of sequence similarity to satisfy statistical significance, the high modality and low complexity of SLiMs can obscure the search for homologous sequences considerably. Due to their limited size (7-12 residues), these motifs can easily develop in unrelated proteins in convergent evolution. Furthermore, post-translational modifications (PTMs) that often regulate IDP function complicate the analysis, as they can drastically alter the biophysical features of a protein and phosphorylation sites display short and weakly conserved motifs that are often difficult to detect via computational sequence analysis [15].Within protein interaction networks, IDPs ofte...

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Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

Cited by 21 publications

References 216 publications

Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation

Endogenous Cyclin D1 Promotes the Rate of Onset and Magnitude of Mitogenic Signaling via Akt1 Ser473 Phosphorylation

Beneficial Actions of Orostachys japonica and Its Compounds against Tumors via MAPK Signaling Pathways

Common Functions of Disordered Proteins across Evolutionary Distant Organisms

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