Apoptosis-induced release of mature sterol regulatory element-binding proteins activates sterol-responsive genes

It is well established that during the execution of the apoptotic cascade, activated caspase 3 releases sterol regulatory element-binding proteins (SREBP) from the membrane of the endoplasmic reticulum in a proteolytic re- action that is distinct from their normal sterol-dependent activation. However, it is not known whether these tran- scription factors are capable of activating sterol-responsive genes under such conditions. The construction of SRE ex- pression vectors has permitted characterization of the apo- ptotic activation of SREBP. Cell lines stably expressing the plasma membrane marker CD32, or GFP, under the control of the SRE promoter were shown to modulate SRE gene ex- pression on the basis of the levels of available sterols. How- ever, during the induction of apoptosis, expression of CD32 and GFP was highly induced, even in the presence of ample sterols. Apoptotic induction of sterol-regulated genes was due to activation of caspase 3 and was impervious to treat- ment with sphingomyelinase, indicating that activation of SRE genes during apoptosis is sterol independent. Further characterization of this apoptotic response indicated that ste- rol-regulated genes are activated at an early stage in the apo- ptotic cascade, preceding the externalization of phosphati- dylserine on the plasma membrane of apoptotic cells. These results suggest that activation of sterol-responsive genes early during apoptosis may play a role in the proper execution of this program. —Higgins, M. E., and Y. A. Ioan- nou. Apoptosis-induced release of mature sterol regulatory element-binding proteins activates sterol-responsive genes. J. Lipid Res. 2001. 42: 1939-1946.