Stimulation of Mitogenesis by a Cell-Permeable PI 3-Kinase Binding Peptide

Derossi, Daniele; Williams, Emma J.; Green, Paula J.; Dunican, Dara J.; Doherty, Patrick

doi:10.1006/bbrc.1998.9444

Cited by 64 publications

(49 citation statements)

References 25 publications

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“…In the present study, using a peptide mimetic of the pTyr domain of the PDGF receptor to increase PI3K activation (Derossi et al, 1998), we show that PI3K activation induces synaptogenic and spinogenic effects on primary cultures of rat hippocampal neurons and also on CA1 hippocampal neurons in vivo. Furthermore, these morphological changes are functional according to the criteria of increased basal neurotransmitter release, and correlate with an enhancement of cognitive behavior in the treated animals.…”

Section: Introductionmentioning

confidence: 53%

Phosphoinositide-3-Kinase Activation Controls Synaptogenesis and Spinogenesis in Hippocampal Neurons

Cuesto

Enriquez-Barreto²,

Caramés³

et al. 2011

J. Neurosci.

123

129

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The possibility of changing the number of synapses may be an important asset in the treatment of neurological diseases. In this context, the synaptogenic role of the phosphoinositide-3-kinase (PI3K) signaling cascade has been previously demonstrated in Drosophila. This study shows that treatment with a PI3K-activating transduction peptide is able to promote synaptogenesis and spinogenesis in primary cultures of rat hippocampal neurons, as well as in CA1 hippocampal neurons in vivo. In culture, the peptide increases synapse density independently of cell density, culture age, dendritic complexity, or synapse type. The induced synapses also increase neurotransmitter release from cultured neurons. The synaptogenic signaling pathway includes PI3K-Akt. Furthermore, the treatment is effective on adult neurons, where it induces spinogenesis and enhances the cognitive behavior of treated animals in a fear-conditioning assay. These findings demonstrate that functional synaptogenesis can be induced in mature mammalian brains through PI3K activation.

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Section: Introductionmentioning

confidence: 53%

Phosphoinositide-3-Kinase Activation Controls Synaptogenesis and Spinogenesis in Hippocampal Neurons

Cuesto

Enriquez-Barreto²,

Caramés³

et al. 2011

J. Neurosci.

123

129

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“…Because of difficulty in performing gene therapy in human, we activated dormant follicles using a PTEN inhibitor and a PI3K activator based on a short-term (2 days) in vitro activation protocol. Previous studies showed that a PTEN inhibitor, bpV, indirectly activates the PI3K-AKT signaling pathway (Posner et al 1994, Bavan et al 1995, Schmid et al 2004, whereas a cell-permeable phosphopeptide, 740Y-P, binds to the SH2 domain of p85 regulatory subunit of PI3K to activate its catalytic subunit (Derossi et al 1998). Using both drugs, we demonstrated that short-term culture of neonatal mouse and human ovaries increased primary follicle numbers via nuclear exclusion of FOXO3 in vitro (Li et al 2010).…”

Section: Development Of New Therapy For Poi Based On Pi3k-akt Signalingmentioning

confidence: 68%

Disorganization of the germ cell pool leads to primary ovarian insufficiency

Kawashima

Kawamura

2017

Reproduction

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The mammalian ovary is an organ that controls female germ cell development, storing them and releasing mature oocytes for transporting to the oviduct. During the fetal stage, female germ cells change from a proliferative state to meiosis before forming follicles with the potential for the growth of surrounding somatic cells. Understanding of molecular and physiological bases of germ cell development in the fetal ovary contributed not only to the elucidation of genetic disorders in primary ovarian insufficiency (POI), but also to the advancement of novel treatments for patients with POI. Accumulating evidence indicates that mutations in NOBOX, DAZL and FIGLA genes are associated with POI. In addition, cell biology studies revealed the important roles of these genes as essential translational factors for germ cell development. Recent insights into the role of the PI3K (phosphatidylinositol 3-kinase)-AKT signaling pathway in primordial follicle activation allowed the development of a new infertility treatment, IVA (in vitro activation), leading to successful pregnancy/delivery in POI patients. Furthermore, elucidation of genetic dynamics underlying female germ cell development could allow regeneration of oocytes from ES (embryonic stem)/iPS (induced pluripotent stem) cells in mammals. The purpose of this review is to summarize basic findings related to female germ cell development and potential clinical implications, especially focusing on POI etiologies. We also summarize evolving new POI therapies based on IVA as well as oocyte regeneration.Reproduction (2017) 153 R205-R213

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“…Ovaries containing mainly primordial follicles were obtained from neonatal mice at day 3 of age. Pairs of ovaries were incubated with bpV(pic) (100 μM) or culture media (control group) for 24 h. In addition to bpV(pic), some ovaries were treated for 48 h with a cell-permeable phospho-peptide (740Y-P) capable of binding to the SH2 domain of the p85 regulatory subunit of PI3K to stimulate enzyme activity (10). Activated PI3K converts phosphatidylinositol (4, 5)-bisphosphate (PIP2) to phosphatidylinositol (3-5)-trisphosphate (PIP3), whereas the PTEN inhibitor prevents the conversion of PIP3 back to PIP2.…”

Section: Resultsmentioning

confidence: 99%

“…The synthetic 740Y-P peptide has a phosphorylated tyrosine residue with flanking sequences identical to the interaction site of activated PDGF receptor, together with a protein transduction domain (16 residues) of the fly Antennapedia protein (25) to facilitate plasma membrane penetration. Peptide 740Y-P is a potent stimulator of PI3K activity and mitogenic responses in myoblast cells (10) and promotes primordial germ cell migration by mimicking the action of the receptor tyrosine kinase c-kit (26). This PI3K-activating peptide likely increases intracellular PIP3 levels, mimicking the effects of ovarian ligands for tyrosine kinase receptors such as kit ligand, PDGF, leukemia inhibitor factor, and neurotrophins (17)(18)(19)27).…”

Section: Discussionmentioning

confidence: 99%

Activation of dormant ovarian follicles to generate mature eggs

Kawamura

Cheng

et al. 2010

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

375

340

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Although multiple follicles are present in mammalian ovaries, most of them remain dormant for years or decades. During reproductive life, some follicles are activated for development. Genetically modified mouse models with oocyte-specific deletion of genes in the PTEN-PI3K-Akt-Foxo3 pathway exhibited premature activation of all dormant follicles. Using an inhibitor of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) phosphatase and a PI3K activating peptide, we found that short-term treatment of neonatal mouse ovaries increased nuclear exclusion of Foxo3 in primordial oocytes. After transplantation under kidney capsules of ovariectomized hosts, treated follicles developed to the preovulatory stage with mature eggs displaying normal epigenetic changes of imprinted genes. After in vitro fertilization and embryo transfer, healthy progeny with proven fertility were delivered. Human ovarian cortical fragments from cancer patients were also treated with the PTEN inhibitor. After xeno-transplantation to immune-deficient mice for 6 months, primordial follicles developed to the preovulatory stage with oocytes capable of undergoing nuclear maturation. Major differences between male and female mammals are unlimited number of sperm and paucity of mature oocytes. Thus, short-term in vitro activation of dormant ovarian follicles after stimulation of the PI3K-Akt pathway allows the generation of a large supply of mature female germ cells for future treatment of infertile women with a diminishing ovarian reserve and for cancer patients with cryo-preserved ovaries. Generation of a large number of human oocytes also facilitates future derivation of embryonic stem cells for regenerative medicine.

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Stimulation of Mitogenesis by a Cell-Permeable PI 3-Kinase Binding Peptide

Cited by 64 publications

References 25 publications

Phosphoinositide-3-Kinase Activation Controls Synaptogenesis and Spinogenesis in Hippocampal Neurons

Phosphoinositide-3-Kinase Activation Controls Synaptogenesis and Spinogenesis in Hippocampal Neurons

Disorganization of the germ cell pool leads to primary ovarian insufficiency

Activation of dormant ovarian follicles to generate mature eggs

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