Cell Cycle Arrest Induced by an Inhibitor of Glucosylceramide Synthase

Rani, C. S. Sheela; Abe, Akira; Chang, Yan; Rosenzweig, Nitsa; Saltiel, Alan R.; Radin, Norman S.; Shayman, James A.

doi:10.1074/jbc.270.6.2859

Cited by 160 publications

(132 citation statements)

References 43 publications

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…4 That said, in support of our observations, a partial ceramide-mediated G 2 /M arrest albeit in the presence of a substantial G 0 /G 1 arrest was reported in W138 human diploid fibroblasts 4 and NIH-3T3 cells. 39 The observed upregulation in p21 Cip1/Waf1 expression described here in the absence of Rb dephosphorylation or the stabilization of p27 Kip1 , which has also been associated with ceramidemediated G 0 /G 1 -arrest, 38 may in part account for the selective arrest of RD cells in the G 2 phase of the cell cycle rather than G 0 /G 1 . Collectively, these data imply that the ceramidemediated modulation of cell cycle progression is cell type specific, and is further dictated to by the basal activity and expression of other cell cycle regulators.…”

Section: Discussionmentioning

confidence: 71%

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

et al. 2007

View full text Add to dashboard Cite

The sphingoplipid ceramide is responsible for a diverse range of biochemical and cellular responses including a putative role in modulating cell cycle progression. Herein, we describe that an accumulation of ceramide, achieved through the exogenous application of C 6 -ceramide or exposure to sphingomyelinase, induces a G 2 arrest in Rhabdomyosarcoma (RMS) cell lines. Utilizing the RMS cell line RD, we show that this G 2 arrest required the rapid induction of p21 Cip1/Waf1 independent of DNA damage. This was followed at later time points (48 h) by the commitment to apoptosis. Apoptosis was prevented by Bcl-2 overexpression, but permitted the maintenance of elevated p21 Cip1/Waf1 protein expression and the stabilization of the G 2 arrest response. Inhibition of p21 Cip1/Waf1 protein synthesis with cyclohexamide (CHX) or silencing of p21 Cip1/Waf1 with siRNA, prevented ceramide-mediated G 2 arrest and the late induction of apoptosis. Further, adopting the recent discovery that murine double minute 2 (MDM2) controls p21 Cip1/Waf1 expression by presenting this CDK inhibitor to the proteasome for degradation, RD cells overexpressing MDM2 abrogated ceramide-mediated p21 Cip1/Waf1 induction, G 2 arrest and the late ensuing apoptosis. Collectively, these data further support the notion that ceramide accumulation can modulate cell cycle progression. Additionally, these observations highlight MDM2 expression and proteasomal activity as key determinants of the cellular response to ceramide accumulation.

show abstract

Section: Discussionmentioning

confidence: 71%

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Furthermore, increased concentration of GlcCer has been implicated in human polycystic kidney disease characterized by hyperproliferative growth of kidney epithelial cells (34). The mechanism by which increased cellular concentration of GlcCer affects cell growth is currently unknown, but it has been speculated that GlcCer directly affects the phosphorylation of cytoplasmic and nuclear cell-cycle proteins (35). Our results suggest that an increase in GlcCer activates the PI3K/Akt pathway either through an effect on a membrane receptor or by affecting membrane signaling platforms.…”

Section: Discussionmentioning

confidence: 99%

Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension

Dahlgaard¹,

Jung

Qvortrup

et al. 2012

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

View full text Add to dashboard Cite

Glycosphingolipids (GSLs) are of fundamental importance in the nervous system. However, the molecular details associated with GSL function are largely unknown, in part because of the complexity of GSL biosynthesis in vertebrates. In Drosophila , only one major GSL biosynthetic pathway exists, controlled by the glycosyltransferase Egghead (Egh). Here we discovered that loss of Egh causes overgrowth of peripheral nerves and attraction of immune cells to the nerves. This phenotype is reminiscent of the human disorder neurofibromatosis type 1, which is characterized by disfiguring nerve sheath tumors with mast cell infiltration, increased cancer risk, and learning deficits. Neurofibromatosis type 1 is due to a reduction of the tumor suppressor neurofibromin, a negative regulator of the small GTPase Ras. Enhanced Ras signaling promotes glial growth through activation of phosphatidylinositol 3-kinase (PI3K) and its downstream kinase Akt. We find that overgrowth of peripheral nerves in egh mutants is suppressed by down-regulation of the PI3K signaling pathway by expression of either dominant-negative PI3K, the tumor suppressor PTEN, or the transcription factor FOXO in the subperineurial glia. These results show that loss of the glycosyltransferase Egh affects membrane signaling and activation of PI3K signaling in glia of the peripheral nervous system, and suggest that glycosyltransferases may suppress proliferation.

show abstract

“…To investigate if the pTyr content of p215 BRCA1 was cellcycle dependent, NIH3T3 cells were arrested at the G 1 /S phase with aphidicolin and at the G 2 /M phase with nocodazole (Rani et al, 1995;Kiyokawa et al, 1995). Compared to normal cycling cells, the pTyr content of p215 BRCA1 was unchanged at the G 1 /S transition, but was higher at the G 2 /M transition ( Figure 4).…”

Section: Examination Of P215 Brca1 Phosphotyrosine Content Changes Dumentioning

confidence: 99%

Relationship of p215BRCA1 to tyrosine kinase signaling pathways and the cell cycle in normal and transformed cells

Zhang

Zhao

et al. 1997

Oncogene

View full text Add to dashboard Cite

We have analysed the relationship of the products of two genes, neu and BRCA1, known to be important in human breast cancer. Highly speci®c antibodies that recognized both the rodent and human form of the BRCA1 gene product (M r 215 kDa, p215 BRCA1 ) were developed to facilitate these e orts. p215 BRCA1 was identi®ed as a tyrosine phosphorylated protein primarily localized in the nucleus of several breast cancer cell lines. In transformed murine and human cells, levels of p215 BRCA1 tyrosine phosphorylation were inversely correlated with the activity of the erbB family receptor-tyrosine-kinases and with the transformed growth features of these cells. Regulation of p215 BRCA1 tyrosine phosphorylation was also related to events in the cell cycle. Increased levels of p215 BRCA1 phosphotyrosine content were observed in NIH3T3 cells arrested at the G 2 /M transition. These ®ndings indicate that the products of BRCA1, neu, and erbB breast cancer genes participate in a common or shared signaling pathway important in cell growth and its regulation.

show abstract

Cell Cycle Arrest Induced by an Inhibitor of Glucosylceramide Synthase

Cited by 160 publications

References 43 publications

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

Ceramide-induced G2 arrest in rhabdomyosarcoma (RMS) cells requires p21Cip1/Waf1 induction and is prevented by MDM2 overexpression

Neurofibromatosis-like phenotype in Drosophila caused by lack of glucosylceramide extension

Relationship of p215BRCA1 to tyrosine kinase signaling pathways and the cell cycle in normal and transformed cells

Contact Info

Product

Resources

About