Spotlight on Geminin

DePamphilis, Melvin L.

doi:10.1186/bcr2881

Cited by 6 publications

(8 citation statements)

References 15 publications

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“…The topoisomerase inhibitor etoposide (VP-16) has been used as a component of combinatorial chemotherapy for newly diagnosed and recurrent medulloblastoma [ 63 - 65 ]. Interestingly, in addition to interacting with Cdt1, Gmnn can interact with Topoisomerase IIα (Topo IIα), a target for etoposide, which resolves chromosomal catenanes formed during DNA replication [ 12 , 66 ]. Gmnn was reported to both promote recruitment of Topo IIα to chromatin during replication and to stimulate its release from chromosomes.…”

Section: Resultsmentioning

confidence: 99%

“…Gmnn was reported to both promote recruitment of Topo IIα to chromatin during replication and to stimulate its release from chromosomes. Accordingly, in some cell contexts, Gmnn over-expression triggers premature Topo IIα release from chromosomes, increasing cellular resistance to the Topo IIα poisons etoposide and doxorubicin, which act by trapping the chromosomally bound transient reaction intermediate [ 12 , 66 ].…”

Section: Resultsmentioning

confidence: 99%

“…Efforts are underway to define small molecules that induce cancer-selective induction of re-replication, cell cycle arrest, and spontaneous apoptosis, by inhibiting the activity of Gmnn or of other molecular controls that prevent excessive DNA replication [ 12 , 78 ]. Our work here demonstrates that, while Gmnn appears largely dispensable for normal neurodevelopment and normal neurological function after early embryogenesis, Gmnn inhibition can impair the growth of both preneoplastic and tumor cells in medulloblastoma, inducing them to undergo a DNA damage response and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…This cancer cell sensitivity to Gmnn loss may involve greater relative ability of non-cancer cell lines to use alternate molecular mechanisms to control Cdt1 activity by proteolysis, and/or relative over-expression of Cdt1 and pre-RC proteins in many cancer cell contexts [ 10 , 11 ]. Based upon these results, it has been proposed that small molecule inhibitors directed against Gmnn may have utility as selective anticancer agents [ 10 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Geminin deficiency enhances survival in a murine medulloblastoma model by inducing apoptosis of preneoplastic granule neuron precursors

et al. 2017

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Medulloblastoma is the most common malignant brain cancer of childhood. Further understanding of tumorigenic mechanisms may define new therapeutic targets. Geminin maintains genome fidelity by controlling re-initiation of DNA replication within a cell cycle. In some contexts, Geminin inhibition induces cancer-selective cell cycle arrest and apoptosis and/or sensitizes cancer cells to Topoisomerase IIα inhibitors such as etoposide, which is used in combination chemotherapies for medulloblastoma. However, Geminin's potential role in medulloblastoma tumorigenesis remained undefined. Here, we found that Geminin is highly expressed in human and mouse medulloblastomas and in murine granule neuron precursor (GNP) cells during cerebellar development. Conditional Geminin loss significantly enhanced survival in the SmoA1 mouse medulloblastoma model. Geminin loss in this model also reduced numbers of preneoplastic GNPs persisting at one postnatal month, while at two postnatal weeks these cells exhibited an elevated DNA damage response and apoptosis. Geminin knockdown likewise impaired human medulloblastoma cell growth, activating G2 checkpoint and DNA damage response pathways, triggering spontaneous apoptosis, and enhancing G2 accumulation of cells in response to etoposide treatment. Together, these data suggest preneoplastic and cancer cell-selective roles for Geminin in medulloblastoma, and suggest that targeting Geminin may impair tumor growth and enhance responsiveness to Topoisomerase IIα-directed chemotherapies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Geminin deficiency enhances survival in a murine medulloblastoma model by inducing apoptosis of preneoplastic granule neuron precursors

et al. 2017

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“…Small molecule transporters were found to be efficient transporters of proteins into cells. These studies utilized geminin, a protein inhibitor of DNA replication (55), as the cargo, and this allowed an easy functional read-out of internalization efficiency. Geminin is easy to clone and purify, and a stable protein to handle (56).…”

Section: Mimics Of Cppsmentioning

confidence: 99%

siRNA Delivery: From Lipids to Cell‐penetrating Peptides and Their Mimics

Gooding¹,

Browne²,

Mota³

et al. 2012

Chem Biol Drug Des

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To deliver siRNA for therapeutic use, several hurdles must be addressed. Metabolic degradation must be blocked, and the RNAi cellular machinery is located in the cytoplasm, while double-stranded siRNA is large, highly charged and impermeable to cell membranes. To date, the solutions to the delivery issues have mostly involved different forms of lipid particle encapsulation. Cell-penetrating peptides and their mimics or analogues offer a different approach and this is an emerging field with the first in vivo examples now reported. Recent reports point to lipid receptors being involved in the cellular uptake of both types of transporter. This review examines the delivery of siRNA with a focus on cellpenetrating peptides and their small molecule and oligomeric mimics. The current status of siRNA delivery methods in clinical trials is examined. It now seems that the goal of delivering siRNA therapeutically is achievable but will they form part of a sustainable healthcare portfolio for the future.

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Regulation of geminin by neuropeptide Y in vascular smooth muscle cell proliferation

Liang

Zhou

Shu

et al. 2018

Herz

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Geminin, a key regulator of DNA replication licensing in the cell cycle, plays an essential role in determining the fate of cells via suppression of cell proliferation and cellular differentiation. Neuropeptide Y (NPY) intensifies the proliferation of vascular smooth muscle cells (VSMCs) directly by binding with Y1 receptors. In vitro experiments have shown that stimulation of NPY on VSMCs via regulation of geminin is a double-edged sword. Given that the proliferation and the phenotypic transformation of VSMCs increase the risk for progression of atherosclerosis, we focus on the role of geminin interference in determining the fate of VSMCs. Furthermore, we discuss the therapeutic potential of peripheral neurotransmitter interference, thus pointing toward future research directions in the treatment of atherosclerosis.

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Spotlight on Geminin

Cited by 6 publications

References 15 publications

Geminin deficiency enhances survival in a murine medulloblastoma model by inducing apoptosis of preneoplastic granule neuron precursors

Geminin deficiency enhances survival in a murine medulloblastoma model by inducing apoptosis of preneoplastic granule neuron precursors

siRNA Delivery: From Lipids to Cell‐penetrating Peptides and Their Mimics

Regulation of geminin by neuropeptide Y in vascular smooth muscle cell proliferation

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