AKAP8 in Mitosis Pathway

Chromatin packaging of the genome is dynamic, changing with the cell cycle and with transcriptional regulation. During mitosis, chromatin is condensed for segregation of chromosomes, while for transcription chromatin is more open. The nuclear matrix, or scaffold, is a protein network in the nucleus providing structure and regulating chromatin condensation. Regulated interactions of matrix proteins with each other, DNA and other factors in different phases of the cell cycle alter the structure and function of chromatin. AKAP95 (A-kinase anchoring protein) is a nuclear matrix associated protein that also binds DNA and different proteins during different phases of the cell cycle. The interaction of AKAP95 with DNA and proteins alters the condensation and transcription of chromatin. A specific domain of AKAP95 regulates its interaction with the nuclear matrix and another regulates its association with DNA. One key protein that AKAP95 interacts with is the cAMP-dependent protein kinase, PKA. AKAP95 binds to PKA through a PKA RII regulatory subunit, an interaction that requires PKA phosphorylation by Cdk1. PKA activity and cAMP are reduced during entry into mitosis, but PKA recruited by AKAP95 to condensed chromosomes is essential to maintain the condensed state. Another protein recruited by AKAP95 is Eg7, a 150 kD protein recruited during mitotic chromatin condensation. Eg7 is a part of a multiprotein condensin complex, recruiting another key component of mitotic chromatin condensation. Modification of the core histones through phosphorylation regulates chromatin condensation. Histone H3 interacts with the condensin complex, and is phosphorylated during mitosis. Histone H3 phosphorylation by Aurora-2 induces chromatin condensation, and dephosphorylation by PP1 promotes chromatin decondensation for reentry into interphase. AKAP95 may play a role during the regulation of chromatin structure for transcription during interphase as well. The interaction of AKAP95 with the p68 RNA helicase recruits this enzyme to the nuclear matrix during interphase. Other nuclear RNA helicases interact with transcription factors and cofactors, suggesting that the p68 RNA helicase also may regulate interactions of transcription complexes. (NCI Thesaurus/BIOCARTA)

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