A Cyclin D2-derived peptide acts on specific cell cycle phases by activating ERK1/2 to cause the death of breast cancer cells

Russo, Lilian Cristina; Araujo, Christiane B. de; Iwai, Leo Kei; Ferro, Emer S.; Forti, Fábio Luís

doi:10.1016/j.jprot.2016.06.028

Cited by 23 publications

(35 citation statements)

References 55 publications

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“…Moreover, when this cyclin D2 α5 helix-derived peptide is fused to a cell-penetrating peptide, the resulting construct, infused in vivo in a rat brain tumor model, reduced the volume of rat C6 glioblastomas by ~50% ( 136 ). Using a fluorescently labeled peptide monitored by real-time confocal microscopy in MDA-MB-231 breast cancer cells, the α5 helix-derived peptide entered the cells within min, localized to the nucleus as well as the cytoplasm, and induced cell death in breast cancer cells, specifically in G1/S-arrested cells and in cells that were actively progressing through S phase ( 137 ).…”

Section: Combinatorial Approaches and Companion Diagnostics For Ccng1mentioning

confidence: 99%

Cell cycle checkpoint control: The cyclin G1/Mdm2/p53 axis emerges as a strategic target for broad‑spectrum cancer gene therapy - A review of molecular mechanisms for oncologists

et al. 2018

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Basic research in genetics, biochemistry and cell biology has identified the executive enzymes and protein kinase activities that regulate the cell division cycle of all eukaryotic organisms, thereby elucidating the importance of site-specific protein phosphorylation events that govern cell cycle progression. Research in cancer genomics and virology has provided meaningful links to mammalian checkpoint control elements with the characterization of growth-promoting proto-oncogenes encoding c-Myc, Mdm2, cyclins A, D1 and G1, and opposing tumor suppressor proteins, such as p53, pRb, p16INK4A and p21WAF1, which are commonly dysregulated in cancer. While progress has been made in identifying numerous enzymes and molecular interactions associated with cell cycle checkpoint control, the marked complexity, particularly the functional redundancy, of these cell cycle control enzymes in mammalian systems, presents a major challenge in discerning an optimal locus for therapeutic intervention in the clinical management of cancer. Recent advances in genetic engineering, functional genomics and clinical oncology converged in identifying cyclin G1 (CCNG1 gene) as a pivotal component of a commanding cyclin G1/Mdm2/p53 axis and a strategic locus for re-establishing cell cycle control by means of therapeutic gene transfer. The purpose of the present study is to provide a focused review of cycle checkpoint control as a practicum for clinical oncologists with an interest in applied molecular medicine. The aim is to present a unifying model that: i) clarifies the function of cyclin G1 in establishing proliferative competence, overriding p53 checkpoints and advancing cell cycle progression; ii) is supported by studies of inhibitory microRNAs linking CCNG1 expression to the mechanisms of carcinogenesis and viral subversion; and iii) provides a mechanistic basis for understanding the broad-spectrum anticancer activity and single-agent efficacy observed with dominant-negative cyclin G1, whose cytocidal mechanism of action triggers programmed cell death. Clinically, the utility of companion diagnostics for cyclin G1 pathways is anticipated in the staging, prognosis and treatment of cancers, including the potential for rational combinatorial therapies.

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Section: Combinatorial Approaches and Companion Diagnostics For Ccng1mentioning

confidence: 99%

Cell cycle checkpoint control: The cyclin G1/Mdm2/p53 axis emerges as a strategic target for broad‑spectrum cancer gene therapy - A review of molecular mechanisms for oncologists

et al. 2018

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“…Some effects of the peptide on tumor cells were found in a previous study (8), and it is known to kill cells that replicate continuously. In addition, the compound exhibits increased action in cells synchronized at S phase of the cell cycle (14). The antiparasitic activity of Pep5-cpp was initially demonstrated in epimastigote forms of two different T. cruzi strains.…”

Section: Discussionmentioning

confidence: 99%

“…This synthetic peptide is a fragment of the HIV TAT protein, which is responsible for promoting its entrance into host cells. Some studies have demonstrated that this specific cpp has great affinity for the nuclear compartment and that it is quickly carried there through the cellular membrane, escaping the endocytic pathway (14,36,37). Thus, Pep5-cpp is rapidly localized to the nuclei of LLC-MK 2 cells and is unavailable for distribution in the cytoplasm and for contact with amastigotes ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…To avoid nonspecific and low-affinity protein binding, the first milliliter eluted was discarded, and the other 9 ml (subjected to buffer exchange in 10 mM Tris-HCl, pH 7.4) was concentrated using a Millipore (Darmstadt, Germany) centrifugal filter device with a cutoff value of 5,000 Da. All proteins (after in᎑solution digestion) that bound to Pep5 or cpp were identified by mass spectrometry using an Easy-nLC nanoflow liquid chromatograph (Thermo Scientific, Waltham, MA, USA), along with an LTQ-Orbitrap Velos mass spectrometer (Thermo Scientific), as previously reported (14).…”

Section: Antimicrobial Agents and Chemotherapymentioning

confidence: 99%

“…Moreover, in vivo experiments showed that the cyclin fragment decreased the rat glioblastoma tumor volume by approximately 50% (8). Pep5 interacts with specific intracellular proteins from human MDA-MB-231 breast cancer cells, especially those associated with cytoskeleton and proteasome components, such as plectin (14). Notably, these proteins, such as chloride intracellular channel protein 1 and plectin, exert antiapoptotic and proliferation inhibition effects (14).…”

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Pep5, a Fragment of Cyclin D2, Shows Antiparasitic Effects in Different Stages of the Trypanosoma cruzi Life Cycle and Blocks Parasite Infectivity

Araujo

Lima

Calderano

et al. 2019

Antimicrob Agents Chemother

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Pep5 (WELVVLGKL) is a fragment of cyclin D2 that exhibits a 2-fold increase in the S phase of the HeLa cell cycle. When covalently bound to a cellpenetrating peptide (Pep5-cpp), the nonapeptide induces cell death in several tumor cells, including breast cancer and melanoma cells. Additionally, Pep5-cpp reduces the in vivo tumor volume of rat glioblastoma. Chagas disease, which is caused by the flagellated parasite Trypanosoma cruzi, is a neglected disease that occurs mainly in the Americas, where it is considered an important public health issue. Given that there are only two options for treating the disease, it is exceptionally crucial to search for new molecules with potential pharmacological action against the parasites. In this study, we demonstrate that Pep5-cpp induces cell death in epimastigote, trypomastigote, and amastigote forms of T. cruzi. The Pep5-cpp peptide was also able to decrease the percentage of infected cells without causing any detectable toxic effects in mammalian host cells. The infective, i.e., trypomastigote form of T. cruzi pretreated with Pep5-cpp was unable to infect LLC-MK 2 monkey kidney cells. Also, Pep5-binding proteins were identified by mass spectrometry, including calmodulinubiquitin-associated protein, which is related to the virulence and parasitemia of T. cruzi. Taken together, these data suggest that Pep5 can be used as a novel alternative for the treatment of Chagas disease.

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Cytoskeleton | Intermediate Filament Linker Proteins: Plectin and BPAG1

Wiche

Castañón

2021

Encyclopedia of Biological Chemistry III

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A Cyclin D2-derived peptide acts on specific cell cycle phases by activating ERK1/2 to cause the death of breast cancer cells

Cited by 23 publications

References 55 publications

Cell cycle checkpoint control: The cyclin G1/Mdm2/p53 axis emerges as a strategic target for broad‑spectrum cancer gene therapy - A review of molecular mechanisms for oncologists

Cell cycle checkpoint control: The cyclin G1/Mdm2/p53 axis emerges as a strategic target for broad‑spectrum cancer gene therapy - A review of molecular mechanisms for oncologists

Pep5, a Fragment of Cyclin D2, Shows Antiparasitic Effects in Different Stages of the Trypanosoma cruzi Life Cycle and Blocks Parasite Infectivity

Cytoskeleton | Intermediate Filament Linker Proteins: Plectin and BPAG1

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