scholarly journals Dephosphorylation and Caspase Processing Generate Distinct Nuclear Pools of Histone Deacetylase 4

2007 ◽  
Vol 27 (19) ◽  
pp. 6718-6732 ◽  
Author(s):  
Gabriela Paroni ◽  
Alessandra Fontanini ◽  
Nadia Cernotta ◽  
Carmela Foti ◽  
Mahesh P. Gupta ◽  
...  
Keyword(s):  
Cell Death ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Proteolytic Processing ◽  
Chromatin Interaction ◽  
Nuclear Accumulation ◽  
Stable Complex ◽  
Extracellular Signals ◽  
Repressive Effect ◽  
Histone Deacetylase 4

ABSTRACT From the nucleus, histone deacetylase 4 (HDAC4) regulates a variety of cellular processes, including growth, differentiation, and survival, by orchestrating transcriptional changes. Extracellular signals control its repressive influence mostly through regulating its nuclear-cytoplasmic shuttling. In particular, specific posttranslational modifications such as phosphorylation and caspase-mediated proteolytic processing operate on HDAC4 to promote its nuclear accumulation or export. To understand the signaling properties of this deacetylase, we investigated its cell death-promoting activity and the transcriptional repression potential of different mutants that accumulate in the nucleus. Here we show that, compared to that of other nuclear forms of HDAC4, a caspase-generated nuclear fragment exhibits a stronger cell death-promoting activity coupled with increased repressive effect on Runx2- or SRF-dependent transcription. However, this mutant displays reduced repressive action on MEF2C-driven transcription. Photobleaching experiments and quantitative analysis of the raw data, based on a two-binding-state compartmental model, demonstrate the existence of two nuclear pools of HDAC4 with different chromatin-binding properties. The caspase-generated fragment is weakly bound to chromatin, whereas an HDAC4 mutant defective in 14-3-3 binding or the wild-type HDAC5 protein forms a more stable complex. The tightly bound species show an impaired ability to induce cell death and repress Runx2- or SRF-dependent transcription less efficiently. We propose that, through specific posttranslation modifications, extracellular signals control two distinct nuclear pools of HDAC4 to differentially dictate cell death and differentiation. These two nuclear pools of HDAC4 are characterized by different repression potentials and divergent dynamics of chromatin interaction.

scholarly journals Regulation of Histone Deacetylase 4 by Binding of 14-3-3 Proteins

2000 ◽  
Vol 20 (18) ◽  
pp. 6904-6912 ◽  
Author(s):  
Audrey H. Wang ◽  
Michael J. Kruhlak ◽  
Jiong Wu ◽  
Nicholas R. Bertos ◽  
Marko Vezmar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Deacetylase ◽  
Nuclear Localization ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Regulatory Mechanism ◽  
Dna Recombination ◽  
Biological Processes ◽  
Histone Deacetylase 4

ABSTRACT Histone (de)acetylation is important for the regulation of fundamental biological processes such as gene expression and DNA recombination. Distinct classes of histone deacetylases (HDACs) have been identified, but how they are regulated in vivo remains largely unexplored. Here we describe results demonstrating that HDAC4, a member of class II human HDACs, is localized in the cytoplasm and/or the nucleus. Moreover, we have found that HDAC4 interacts with the 14-3-3 family of proteins that are known to bind specifically to conserved phosphoserine-containing motifs. Deletion analyses suggested that S246, S467, and S632 of HDAC4 mediate this interaction. Consistent with this, alanine substitutions of these serine residues abrogated 14-3-3 binding. Although these substitutions had minimal effects on the deacetylase activity of HDAC4, they stimulated its nuclear localization and thus led to enhanced transcriptional repression. These results indicate that 14-3-3 proteins negatively regulate HDAC4 by preventing its nuclear localization and thereby uncover a novel regulatory mechanism for HDACs.

scholarly journals The role of histone deacetylase 4 during chondrocyte hypertrophy and endochondral bone development

2020 ◽  
Vol 9 (2) ◽  
pp. 82-89 ◽  
Author(s):  
Zhi Chen ◽  
Zhiwei Zhang ◽  
Li Guo ◽  
Xiaochun Wei ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Bone Development ◽  
Chromatin Condensation ◽  
Negative Regulator ◽  
Endochondral Bone Formation ◽  
Endochondral Bone ◽  
Chondrocyte Hypertrophy ◽  
Histone Deacetylase 4

Chondrocyte hypertrophy represents a crucial turning point during endochondral bone development. This process is tightly regulated by various factors, constituting a regulatory network that maintains normal bone development. Histone deacetylase 4 (HDAC4) is the most well-characterized member of the HDAC class IIa family and participates in different signalling networks during development in various tissues by promoting chromatin condensation and transcriptional repression. Studies have reported that HDAC4-null mice display premature ossification of developing bones due to ectopic and early-onset chondrocyte hypertrophy. Overexpression of HDAC4 in proliferating chondrocytes inhibits hypertrophy and ossification of developing bones, which suggests that HDAC4, as a negative regulator, is involved in the network regulating chondrocyte hypertrophy. Overall, HDAC4 plays a key role during bone development and disease. Thus, understanding the role of HDAC4 during chondrocyte hypertrophy and endochondral bone formation and its features regarding the structure, function, and regulation of this process will not only provide new insight into the mechanisms by which HDAC4 is involved in chondrocyte hypertrophy and endochondral bone development, but will also create a platform for developing a therapeutic strategy for related diseases. Cite this article: Bone Joint Res. 2020;9(2):82–89.

Nuclear accumulation of histone deacetylase 4 (HDAC4) by PP1-mediated dephosphorylation exerts neurotoxicity in Pb-exposed neural cells

2020 ◽  
Vol 81 ◽  
pp. 395-405
Author(s):  
Xiaozhen Gu ◽  
Xiyao Huang ◽  
Danyang Li ◽  
Nanxi Bi ◽  
Xi Yu ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Nuclear Accumulation ◽  
Neural Cells ◽  
Histone Deacetylase 4

scholarly journals DNase II mediates a parthanatos-like developmental cell death pathway in Drosophila primordial germ cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lama Tarayrah-Ibraheim ◽  
Elital Chass Maurice ◽  
Guy Hadary ◽  
Sharon Ben-Hur ◽  
Alina Kolpakova ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Germ Cells ◽  
Nuclear Translocation ◽  
Primordial Germ Cells ◽  
Nuclear Accumulation ◽  
Dependent Manner ◽  
Dnase Ii ◽  
Cell Death Pathway ◽  
Parp 1

AbstractDuring Drosophila embryonic development, cell death eliminates 30% of the primordial germ cells (PGCs). Inhibiting apoptosis does not prevent PGC death, suggesting a divergence from the conventional apoptotic program. Here, we demonstrate that PGCs normally activate an intrinsic alternative cell death (ACD) pathway mediated by DNase II release from lysosomes, leading to nuclear translocation and subsequent DNA double-strand breaks (DSBs). DSBs activate the DNA damage-sensing enzyme, Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) and the ATR/Chk1 branch of the DNA damage response. PARP-1 and DNase II engage in a positive feedback amplification loop mediated by the release of PAR polymers from the nucleus and the nuclear accumulation of DNase II in an AIF- and CypA-dependent manner, ultimately resulting in PGC death. Given the anatomical and molecular similarities with an ACD pathway called parthanatos, these findings reveal a parthanatos-like cell death pathway active during Drosophila development.

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