Chromatin compaction and cell death by high molecular weight FGF-2 depend on its nuclear localization, intracrine ERK activation, and engagement of mitochondria

Fibroblast growth factor 2 (FGF‐2) is produced as CUG‐initiated, 22–34 kDa or AUG‐initiated 18 kDa isoforms (hi‐ and lo‐FGF‐2, respectively), with potentially distinct functions. We report that expression of hi‐FGF‐2 in HEK293 cells elicited chromatin compaction preceding cell death with apoptotic features. Nuclear localization of the intact protein was required as expression of a non‐nuclear hi‐FGF‐2 mutant failed to elicit chromatin compaction. Equally ineffective, despite nuclear localization, was the over‐expression of the 18 kDa core sequence (lo‐FGF‐2). Chromatin compaction by hi‐FGF‐2 was accompanied by increased cytosolic cytochrome C, and was attenuated either by over‐expression of Bcl‐2 or by a peptide inhibitor of the pro‐apoptotic protein Bax. In addition hi‐FGF‐2 elicited sustained activation of total and nuclear extracellular signal regulated kinase (ERK1/2) by an intracrine route, as it was not prevented by neutralizing anti‐FGF‐2 antibodies. Inhibition of the ERK1/2 activating pathway by dominant negative upstream activating kinase, or by PD 98059, prevented chromatin compaction by hi‐FGF‐2. ERK1/2 activation was not affected by the Bax‐inhibiting peptide suggesting that it occurred upstream of mitochondrial involvement. We conclude that the hi‐FGF‐2‐induced chromatin compaction and cell death requires its nuclear localization, intracrine ERK1/2 activation and mitochondrial engagement. J. Cell. Physiol. 213:690–698. © 2007 Wiley‐Liss, Inc.