A novel isoform of prostate apoptosis response 4 (PAR-4) that co-distributes with F-actin and prevents apoptosis in neural stem cells

2010

Neurochem Res

Dr. Robert K. Yu's research showed for the first time that the composition of glycosphingolipids is tightly regulated during embryo development. Studies in our group showed that the glycosphingolipid precursor ceramide is also critical for stem cell differentiation and apoptosis. Our new studies suggest that ceramide and its derivative, sphingosine-1-phosphate (S1P), act synergistically on embryonic stem (ES) cell differentiation. When using neural precursor cells (NPCs) derived from ES cells for transplantation, residual pluripotent stem (rPS) cells pose a significant risk of tumor formation after stem cell transplantation. We show here that rPS cells did not express the S1P receptor S1P1, which left them vulnerable to ceramide or ceramide analog (N-oleoyl serinol or S18)-induced apoptosis. In contrast, ES cell-derived NPCs expressed S1P1 and were protected in the presence of S1P or its pro-drug analog FTY720. Consistent with previous studies, FTY720-treated NPCs differentiated predominantly toward oligodendroglial lineage as tested by the expression of the oligodendrocyte precursor cell (OPC) markers Olig2 and O4. As the consequence, a combined administration of S18 and FTY720 to differentiating ES cells eliminated rPS cells and promoted oligodendroglial differentiation. In addition, we show that this combination promoted differentiation of ES cell-derived NPCs toward oligodendroglial lineage in vivo after transplantation into mouse brain.

Section: Discussionmentioning

confidence: 99%

There is More to a Lipid than just Being a Fat: Sphingolipid-Guided Differentiation of Oligodendroglial Lineage from Embryonic Stem Cells

2010

Neurochem Res

“…In this regard, it may be of interest that PAR-4 has been found to be temporarily associated with the actin cytoskeleton [136] . Our group has described a short form of PAR-4 that acts as dominant negative regulator of apoptosis by forming actin-associated heterodimers with the pro-apoptotic long form of PAR-4 [6] .…”

Section: Lipid Rafts and Slips: A Platform For Cell Signaling Pathwaysmentioning

confidence: 99%

“…For example, if cells express high levels of prostate apoptosis response 4 (PAR-4), an inhibitor protein of aPKC, ceramide will induce binding of PAR-4 to aPKC. PAR-4-mediated inhibition of aPKC will then result in apoptosis [2,[4][5][6] . If cells express low levels of PAR-4, ceramide will promote association of the small GTPase Cdc42 with aPKC and sustain cell polarity [3] .…”

Section: Introduction and Overviewmentioning

confidence: 99%

Smart Drugs for Smarter Stem Cells: Making SENSe (Sphingolipid-Enhanced Neural Stem Cells) of Ceramide

2008

Neurosignals

Ceramide and its derivative sphingosine-1-phosphate (S1P) are important signaling sphingolipids for neural stem cell apoptosis and differentiation. Most recently, our group has shown that novel ceramide analogs can be used to eliminate teratoma (stem cell tumor)-forming cells from a neural stem cell graft. In new studies, we found that S1P promotes survival of specific neural precursor cells that undergo differentiation to cells expressing oligodendroglial markers. Our studies suggest that a combination of novel ceramide and S1P analogs eliminates tumor-forming stem cells and at the same time, triggers oligodendroglial differentiation. This review discusses recent studies on the function of ceramide and S1P for the regulation of apoptosis, differentiation, and polarity in stem cells. We will also discuss results from ongoing studies in our laboratory on the use of sphingolipids in stem cell therapy.

“…It was also known that aPKC interaction with an endogenous inhibitor protein, prostate apoptosis response-4 (PAR-4) previously discovered in prostate cancer cells, induces apoptosis [123–125]. We demonstrated for the first time that ceramide activates and enhances autophosphorylation of aPKC in cells, but also induces inactivation of aPKC when PAR-4 expression is elevated [108, 111, 126–129]. Moreover, we showed that this mechanism (sensitizing cells to ceramide by expressing PAR-4) eliminates teratoma (stem cell tumor)-forming stem cells from differentiating ES cells and may also control the number of neural progenitors during brain development [126, 128].…”

Section: Lipid Mediators That Affect Protein Kinase Cascades and Ementioning

confidence: 96%

It’s a Lipid’s World: Bioactive Lipid Metabolism and Signaling in Neural Stem Cell Differentiation

2012

Neurochem Res

Lipids are often considered membrane components whose function is to embed proteins into cell membranes. In the last two decades, studies on brain lipids have unequivocally demonstrated that many lipids have critical cell signaling functions; they are called “bioactive lipids”. Pioneering work in Dr. Robert Ledeen’s laboratory has shown that two bioactive brain sphingolipids, sphingomyelin and the ganglioside GM1 are major signaling lipids in the nuclear envelope. In addition to derivatives of the sphingolipid ceramide, the bioactive lipids discussed here belong to the classes of terpenoids and steroids, eicosanoids, and lysophospholipids. These lipids act mainly through two mechanisms: 1) direct interaction between the bioactive lipid and a specific protein binding partner such as a lipid receptor, protein kinase or phosphatase, ion exchanger, or other cell signaling protein; and 2) formation of lipid microdomains or rafts that regulate the activity of a group of raft-associated cell signaling proteins. In recent years, a third mechanism has emerged, which invokes lipid second messengers as a regulator for the energy and redox balance of differentiating neural stem cells (NSCs). Interestingly, developmental niches such as the stem cell niche for adult NSC differentiation may also be metabolic compartments that respond to a distinct combination of bioactive lipids. The biological function of these lipids as regulators of NSC differentiation will be reviewed and their application in stem cell therapy discussed.