Abstract
Fibroblast growth factor 2 (FGF2) is a multifunctional cell growth factor that regulates cell proliferation, differentiation, adhesion, migration, and apoptosis. FGF2 has multiple isoforms, including an 18‐kDa low molecular weight isoform (lo‐FGF2) and 22‐, 23‐, 24‐, and 34‐kDa high molecular weight isoforms (hi‐FGF2). Hi‐FGF2 overexpression induces chromatin compaction, which requires the mitochondria and leads to apoptosis. Complement component 1 Q subcomponent–binding protein (C1QBP) plays an important role in mitochondria‐dependent apoptosis by regulating the opening of the mitochondrial permeability transition pore. However, the interaction between C1QBP and hi‐FGF2 and its role in hi‐FGF2–mediated apoptosis remain unclear. Here, we found that hi‐FGF2 overexpression induced depolarization of the mitochondrial membrane, cytochrome c release into the cytosol, and a considerable increase in C1QBP messenger RNA and protein expression. Furthermore, coimmunoprecipitation results showed that the mitochondrial protein, C1QBP, interacts with hi‐FGF2. C1QBP knockdown using small interfering RNA significantly decreased the localization of hi‐FGF2 to the mitochondria and increased the rate of apoptosis. Our results highlight a novel mechanism underlying hi‐FGF2–induced, mitochondria‐driven cell death involving the direct interaction between hi‐FGF2 and C1QBP and the upregulation of C1QBP expression.
Highlights
Fibroblast growth factor 2 (FGF2) is expressed as an AUG‐initiated 18‐kDa isoform or CUG‐initiated 21 to 34 kDa isoforms, whose levels vary depending on cell and tissue type and developmental stage.[1]
The rate of decrease in mitochondrial hi‐FGF2 levels was proportional to the decrease in component 1 Q subcomponent–binding protein (C1QBP) levels. These results show that hi‐FGF2 and C1QBP colocalize in the mitochondria and suggest that hi‐FGF2‐C1QBP interactions may be important for hi‐FGF2 mitochondrial localization
Our results are consistent with those of a previous study that showed that increased hi‐FGF2 expression in NIH3T3 fibroblasts upregulated the expression of genes involved in cell‐cycle arrest, such as NFLX and NUPR1, and tumor suppression, such as ST5.13,14 hi‐FGF2 induces chromatin compaction and cell death by activating the mitochondria‐mediated proapoptotic pathway.[14]
Summary
Fibroblast growth factor 2 (FGF2) is expressed as an AUG‐initiated 18‐kDa isoform (lo‐FGF2) or CUG‐initiated 21 to 34 kDa isoforms (hi‐FGF2), whose levels vary depending on cell and tissue type and developmental stage.[1]. Overexpression of hi‐FGF2, but not lo‐FGF2, significantly increases binucleation and the formation of compacted chromatin clumps, a unique nuclear phenotype, in an intracrine manner.[8,9] Hi‐FGF2–associated chromatin compaction in cardiomyocytes appears to reflect the direct effects of hi‐ FGF2 on chromatin structure that does not require mitosis.[10] the isoproterenol‐induced increase in the transient expression of endogenous hi‐FGF2 and the induction of cell death suggest that increased levels of hi‐FGF2 exert cytotoxic effects.[11] The intracrine activity of hi‐FGF2 induces mitotic arrest, chromatin disruption, and cell loss and promotes the appearance of a DNA ladder, presumably due to apoptosis.[12] A complementary DNA (cDNA) microarray–based study[13] demonstrated that hi‐FGF2 expression in NIH3T3 fibroblasts upregulated the expression of genes associated with cell‐cycle arrest, such as NFLX and NUPR1, and tumor suppression, such as ST5.
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