Histone deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and its cellular localization is regulated by oncogenic Ras

Histone deacetylase 4 (HDAC4) is a member of a family of enzymes that catal yze the removal of acetyl groups from core histones, resulting in a compact chromatin structure that is generally associated with repressed gene trans cription. Protein phosphorylation has been implicated in the regulation of the corepressor activity of the deacetylase, Here we report that serine/thr eonine kinases are found in association with HDAC4 and phosphorylate HDAC4 in vitro, and HDAC4 is phosphorylated in cells. The extracellular signal-re gulated kinases 1 and 2 (ERK1/2), also known as p44(MAPK) and p42(MAPK), re spectively, are two of the kinases associated with HDAC4. ERK1/2 a re compo nents of the Ras-mitogen-activated protein kinase (MAPK) signal transductio n pathway. Activation of the Ras-MAPK pathway by expression of oncogenic Pa s or constitutively active MAPK/ERK kinase 1 results in an increased percen tage of cells (from approximate to 10% to approximate to 70%) that express HDAC4 in the nucleus in C2C12 myoblast cells. In cells transfected with onc ogenic Pas, nuclear HDAC4 is associated with kinase activity. Our results p rovide evidence that protein kinase activity is present in a protein comple x with HDAC4 and directly links the Ras-MAPK signal transduction pathway to a mechanism for chromatin remodeling (i.e., histone deacetylation).