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The C-terminal domain (CTD) in linker histones antagonizes anti-apoptotic proteins to modulate apoptotic outcomes at the mitochondrion.

ABSTRACT: The loss of mitochondrial integrity as a consequence of apoptogenic complexes formed on the outer membrane constitutes a key step in controlling progression of apoptotic cascades. Here, we show that multiple members of the linker histone (LH) family of proteins modify apoptotic cascades initiated by the Bcl-2 protein Bak, and impart resistance to its endogenous antagonist Bcl-xL. Our experiments reveal apoptogenic capabilities equivalent to those documented for H1.2 in H1.1 and H1.3 isoforms. Deletion mutants of H1.2 and site-directed mutagenesis of H1.1 and H1.2 implicated the C-terminal domain in apoptogenic activity. In this context, disruption of protein kinase-C activity using chemical inhibitors, dominant-negative approaches and RNA interference coupled with site-directed modifications in H1.1, identified the protein kinase-C?1 isoform as a repressor of H1.1/H1.3 apoptogenic activity. Finally, a H1.2 C-terminal tail recombinant attenuated Bcl-xl inhibition of Bak-induced apoptosis, suggesting that the C-terminal domain was necessary and sufficient for apoptogenic functions. Thus, integration with apoptotic intermediates (via C-terminal tail interactions) may constitute a more generalized function of LH isoforms in apoptotic cascades.

SUBMITTER: Garg M

PROVIDER: S-EPMC3944238 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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The C-terminal domain (CTD) in linker histones antagonizes anti-apoptotic proteins to modulate apoptotic outcomes at the mitochondrion.

Garg M M Ramdas N N Vijayalakshmi M M Shivashankar G V GV Sarin A A

Cell death & disease 20140213

The loss of mitochondrial integrity as a consequence of apoptogenic complexes formed on the outer membrane constitutes a key step in controlling progression of apoptotic cascades. Here, we show that multiple members of the linker histone (LH) family of proteins modify apoptotic cascades initiated by the Bcl-2 protein Bak, and impart resistance to its endogenous antagonist Bcl-xL. Our experiments reveal apoptogenic capabilities equivalent to those documented for H1.2 in H1.1 and H1.3 isoforms. De ...[more]

PMID: 24525734

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Project description:Fibroblast growth factor 1 (FGF1) is a prototypic member of the FGFs family overexpressed in various tumors. Contrarily to most FGFs, FGF1 lacks a secretion peptide signal and acts mainly in an intracellular and nuclear manner. Intracellular FGF1 induces cell proliferation, differentiation and survival. We previously showed that intracellular FGF1 induces neuronal differentiation and inhibits both p53- and serum-free-medium-induced apoptosis in PC12 cells. FGF1 nuclear localization is required for these intracellular activities, suggesting that FGF1 regulates p53-dependent apoptosis and neuronal differentiation by new nuclear pathways. To better characterize intracellular FGF1 pathways, we studied the effect of three mutations localized in the C-terminal domain of FGF1 (i.e., FGF1(K132E), FGF1(S130A) and FGF1(S130D)) on FGF1 neurotrophic and anti-apoptotic activities in PC12 cells. The change of the serine 130 to alanine precludes FGF1 phosphorylation, while its mutation to aspartic acid mimics phosphorylation. These FGF1 mutants kept both a nuclear and cytosolic localization in PC12 cells. Our study highlights for the first time the role of FGF1 phosphorylation and the implication of FGF1 C-terminal domain on its intracellular activities. Indeed, we show that the K132E mutation inhibits both the neurotrophic and anti-apoptotic activities of FGF1, suggesting a regulatory activity for FGF1 C terminus. Furthermore, we observed that both FGF1(S130A) and FGF1(S130D) mutant forms induced PC12 cells neuronal differentiation. Therefore, FGF1 phosphorylation does not regulate FGF1-induced differentiation of PC12 cells. Then, we showed that only FGF1(S130A) protects PC12 cells against p53-dependent apoptosis, thus phosphorylation appears to inhibit FGF1 anti-apoptotic activity in PC12 cells. Altogether, our results show that phosphorylation does not regulate FGF1 neurotrophic activity but inhibits its anti-apoptotic activity after p53-dependent apoptosis induction, giving new insight into the poorly described FGF1 intracrine/nuclear pathway. The study of nuclear pathways could be crucial to identify key regulators involved in neuronal differentiation, tumor progression and resistances to radio- and chemo-therapy.

Dataset Information

The C-terminal domain (CTD) in linker histones antagonizes anti-apoptotic proteins to modulate apoptotic outcomes at the mitochondrion.

Publications

The C-terminal domain (CTD) in linker histones antagonizes anti-apoptotic proteins to modulate apoptotic outcomes at the mitochondrion.

Similar Datasets

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