Hypoxia induces Wee1 expression and attenuates hydrogen peroxide-induced endothelial damage in MS1 cells

Abstract

Abbreviations: cdc2, cell division cycle 2; cdk1, cycle dependent kinase 1; HIF-1α, hypoxia inducible factor-1α; Hsp, heat shock protein AbstractIn an oxygen-depleted environment, endothelial cells initiate an adaptive pattern of synthesis, which may enable them to survive hypoxic crises. Using high-resolution two-dimensional gel electrophoresis in conjunction with mass spectroscopy, we obtained a 24 differential display of proteins in the pancreatic endothelial cell line, MS-1, at four time points following induction of hypoxia. The induction of Wee1 under hypoxia was confirmed both at the mRNA and protein levels. The phosphorylation of cell division cycle 2, which is downstream of Wee1, was also increased after hypoxic exposure. In addition, pre-exposure to hypoxia attenuated a decrease in hydrogen peroxide-induced cell number. The induction of bax (a pro-apoptotic protein) and reduction of bcl (an anti-apoptotic protein) after hypoxia stimulus were also attenuated by hypoxic pre-exposure. Moreover, hydrogen peroxide-induced morphologic damage did not appear in the wild-type Wee1-expressing cells. Taken together, our results suggest that Wee1 may have important role in hypoxia-induced pathophysiological situations in endothelial cells.

Inhibitory effects of scoparone from chestnut inner shell on platelet‐derived growth factor‐BB‐induced vascular smooth muscle cell migration and vascular neointima hyperplasia

“…ERK1/2 is also a key signaling molecule for PDGF‐BB‐induced migration and proliferation and its activation was stimulated by PDGF‐BB in RASMCs . Treatment with an ERK1/2 inhibitor resulted in reduction of PDGF‐BB‐induced migration in RASMCs . Moreover, the present study demonstrated that the PDGF‐BB‐mediated increase in phosphorylation of ERK1/2 was reduced by treatment with scoparone, which inhibited PDGF‐BB‐stimulated RASMC migration; this implies that scoparone may induce the down‐regulation of PDGF‐BB‐stimulated migration, probably through activation of the inhibition of ERK1/2 signaling.…”

“…MAPK activation is a critical event in the stimulation of VSMC proliferation and migration in response to PDGF‐BB . p38 MAPK phosphorylation was increased in RASMCs after treatment with PDGF‐BB; this was involved in PDGF‐BB‐induced RASMC migration, which was attenuated in the absence of p38 MAPK inhibitor . These findings indicate that the PDGF‐BB‐stimulated migration of VSMCs is mediated by p38 MAPK activation.…”

Lactate Influences the Gene Expression Profile of Human Mesenchymal Stem Cells (hMSC) in a Dose Dependant Manner

“…It has been shown that MK-1775, a potent WEE1 inhibitor is able to achieve tumor regressions selectively in p53-deficient pancreatic cancer xenografts [39]. Recently Hong et al could show that hypoxia induces the WEE1 expression both at mRNA and protein levels [40]. We found the expression of WEE1 under normoxicconditions only moderately up regulated at 10 mM lactate, whereas at 5 respectively 15 mM lactate the expression was even more up regulated.…”

Combinations of Kinase Inhibitors Protecting Myoblasts against Hypoxia

“…One of the main regulators of CDKs expression, Notch, has also been reported to play an important role in the response to hypoxia [ 42 , 43 ] and is a critical regulator of cell fate decisions in muscle progenitors [ 44 , 45 ]. Additionally it has been shown that upon hypoxia another cell cycle regulatory kinase, WEE1, a target of the most efficient inhibitor P17, is rapidly activated [ 46 ]. WEE1 is a tyrosine kinase that phosphorylates cdc25 at the G2/M checkpoint and prevents the progression to mitosis [ 47 ].…”