HDAC4 inhibits cell-cycle progression and protects neurons from cell death

Nazanin Majdzadeh, Lulu Wang, Brad E. Morrison, Rhonda Bassel-Duby, Eric N. Olson, Santosh R. D'Mello

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

HDAC4 is a Class II histone deacetylase (HDAC) that is highly expressed in the brain, but whose functional significance in the brain is not known. We show that forced expression of HDAC4 in cerebellar granule neurons protects them against low potassium-induced apoptosis. HDAC4 also protects HT22 neuroblastoma cells from death induced by oxidative stress. HDAC4-mediated neuroprotection does not require its HDAC catalytic domain and cannot be inhibited by chemical inhibitors of HDACs. Neuroprotection by HDAC4 also does not require the Raf-MEK-ERK or the PI-3 kinase-Akt signaling pathways and occurs despite the activation of c-jun, an event that is generally believed to condemn neurons to die. The protective action of HDAC4 occurs in the nucleus and is mediated by a region that contains the nuclear localization signal. HDAC4 inhibits the activity of cyclin-dependent kinase-1 (CDK1) and the progression of proliferating HEK293T and HT22 cells through the cell cycle. Mice-lacking HDAC4 have elevated CDK1 activity and display cerebellar abnormalities including a progressive loss of Purkinje neurons postnatally in posterior lobes. Surviving Purkinje neurons in these lobes have duplicated soma. Furthermore, large numbers of cells within these affected lobes incorporate BrdU, indicating cell-cycle progression. These abnormalities along with the ability of HDAC4 to inhibit CDK1 and cell-cycle progression in cultured cells suggest that neuroprotection by HDAC4 is mediated by preventing abortive cell-cycle progression.

Original languageEnglish (US)
Pages (from-to)1076-1092
Number of pages17
JournalDevelopmental Neurobiology
Volume68
Issue number8
DOIs
StatePublished - Jul 2008

Fingerprint

CDC2 Protein Kinase
Cell Cycle
Cell Death
Neurons
Histone Deacetylases
Purkinje Cells
Nuclear Localization Signals
Histone Deacetylase Inhibitors
Mitogen-Activated Protein Kinase Kinases
Brain
Carisoprodol
Bromodeoxyuridine
Neuroblastoma
Phosphatidylinositol 3-Kinases
Cultured Cells
Catalytic Domain
Potassium
Oxidative Stress
Cell Count
Apoptosis

Keywords

  • Apoptosis
  • Cell cycle
  • HDAC4
  • Histone deacetylase
  • Neuronal survival

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Developmental Neuroscience

Cite this

HDAC4 inhibits cell-cycle progression and protects neurons from cell death. / Majdzadeh, Nazanin; Wang, Lulu; Morrison, Brad E.; Bassel-Duby, Rhonda; Olson, Eric N.; D'Mello, Santosh R.

In: Developmental Neurobiology, Vol. 68, No. 8, 07.2008, p. 1076-1092.

Research output: Contribution to journalArticle

Majdzadeh, Nazanin ; Wang, Lulu ; Morrison, Brad E. ; Bassel-Duby, Rhonda ; Olson, Eric N. ; D'Mello, Santosh R. / HDAC4 inhibits cell-cycle progression and protects neurons from cell death. In: Developmental Neurobiology. 2008 ; Vol. 68, No. 8. pp. 1076-1092.
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