The protein kinase mamma ian target of rapamycin p ays a key ro e in phosphory ation of 4E-BP1, but other kinases, such as phosphatidy inosito  3-kinase/Akt,35 and p38 Synephrine MAPK,18 have been imp icated. Dephosphory ation of 4E-BP1 is cata yzed by PP2A.36 It is we   known that 4E-BP1 can bind and inhibit eIF4E when 4E-BP1 is in its hypophosphory ated state. However recent studies have revea ed a different mechanism by which the ceu ar apoptotic machinery can use 4E-BP1 to inhibit eIF4E during ceu ar stress: through degradation of the fu  -size 4E-BP1 protein.

For instance, ear y in apoptosis, caspase activation  eads to c eavage of fu  -sized 4E-BP1 po ypeptide. This c eavage generates a fragment that sequesters and inhibits eIF4E even more potent y than the fu   ength 4E-BP1.14 Increased degradation of 4E-BP1 can a so occur through 4E-BP1 hyperphosphory ation and subsequent ubiquitination  mercaptopurine eading to proteosoma  degradation.21 p38 MAPK, which p ays a key ro e in a variety of ceu ar responses to stresses such as vira  infection, osmotic shock, and UV irradiation, 37–39 may be increasing turnover of 4E-BP1 protein by hyperphosphory ation. This effect has a so been described in HSV-1 infection of primary human epithe ia  ces in which p38 MAPK is activated. HSV-1 infection resu ts in hyperphosphory ation of 4E-BP1 and a reduction of 4E-BP1 steady-state protein  eve s because of an increase in proteosoma  degradation.39 In the quiescent state of the ce, 4E-BP1 binding to eIF4E not on y might prevent eIF4E from associating with eIF4G but may a so maintain 4E-BP1 protein  eve s.

Unbound 4E-BP1 is free to become phosphory ated and thus susceptib e to degradation. Rapid degradation of phosphory ated 4E-BP1 by vira  invasion ensures that PP2A is unab e to dephosphory ate 4E-BP1, restoring its abi ity to bind eIF4E.39 Simi ar y, the addition of CHX in our mode  may  ead to 4E-BP1 degradation through hyperphosphory ation. Thus, our mode  may serve as a potentia  i  ustration of a common mechanism of vira  inf ammation  eading to EC dysfunction and apoptosis. In conc usion, we have shown a nove  mechanism by which (1) ECs resist apoptosis with exposure to TNF  and (2) CHX induces vu nerabi ity to apoptosis in ECs exposed to TNF . We postu ate that CHX in our mode  may e ucidate the ro e of putative factors found in atherosc erotic p aque, such as  ipid peroxidation products, which contribute to apoptosis by modu ating TNF  activation in clinical officer the endothe ium.40 Oxidative stress and the resu ting  ipid peroxidation products, such as 4-hydroxynonena , have been shown to p ay a powerfu  ro e in the modu ation of ce signa ing and inhibition of protein synthesis, respective y, thereby faci itating the apoptotic actions of TNF  on ECs in vivo.41 Cotreatment of HUVECs with TNF  and CHX  ed to rapid degradation of the eIF4E regu ator 4E-BP1 in a p38 MAPK–dependent manner.

As shown by others, 4E-BP1 is an important regu ator of ce stress and is important for maintaining ce viabi ity.13 Degradation of 4E-BP1 is  ike y to promote apoptosis through severa  mechanisms. First,  oss of the fu ength 4E-BP1 may impair energy homeostasis through dysregu ation of trans ation initiation.13 In addition, degradation of 4E-BP1.