Figure 8.

Model for regulation of HDAC4 activity by cellular localization. Binding of phosphorylated HDAC4 or HDAC5 to 14-3-3 sequesters these proteins in the cytoplasm, where they cannot function in repression of transcription. Dephosphorylation allows HDAC4 and HDAC5 to shuttle to the nucleus, where they associate with HDAC3 and the MEF2 transcription factor, and silence transcription of MEF2-dependent genes. Treatment of cells with the phosphatase inhibitor calyculin A also disrupts the interaction of HDAC3 with HDAC4 and HDAC5 by an unknown mechanism, possibly involving additional protein factors.