19 Dec

Involvement of Histone H3 (Ser10) Phosphorylation in Chromosome: INTRODUCTION

INTRODUCTION

The meiotic resumption of oocytes is controlled by protein kinase MPF (maturation-promoting factor or M-phase promoting factor), which is now also known as Cdc2 kinase. Cdc2 kinase is activated around the germinal vesicle breakdown (GVBD) of oocytes and has been thought to be the key regulator of such major morphological changes during oocyte maturation as chromosome condensation and GVBD and spindle formation. Mitogen-activated protein (MAP) kinase, also termed extracellular signal-regulated kinase (ERK1/ERK2 in mammals), is another kinase known to become activated during oocyte maturation in a number of species, including Xenopus, clams, and also in mammalian species, such as mice, pigs, goats, cattle, and humans. The role of MAP kinase during oocyte maturation has not been firmly established, although it is known that its activation modulates microtubule dynamics.

Chromosome condensation is the first step of oocyte maturation. It is a unique process characterized by a dramatic change in chromosome morphology and is required for the correct segregation of chromosomes during oocyte maturation. The precise change in the nucleus in pig oocytes during maturation was described by Motlik and Fulka. Fully grown pig oocytes have a condensed heterochromatin ring around the nucleolus in the germinal vesicle (GV). When the oocytes resume meiosis in vitro and in vivo, chromosomes start to condense before GVBD. Although the chromosome condensation has been thought to be induced by Cdc2 kinase, recent findings show that the chromosome condensation does not always correlate with Cdc2 kinase activity and that MAP kinase substitutes for the role of Cdc2 kinase. However, the cause of the chromosome condensation has not been completely understood.

The chromatin fiber is composed of repetitive units, the nucleosomes, which are comprised of an octamer of two each of the core histones H2A, H2B, H3, and H4, around which 200 base pairs of DNA are wrapped. Each his-tone contains an N-terminal tail domain, which is involved in the stabilization of the chromatin fiber. The phosphorylation of histone H3 is thought to be involved in transcriptional activation and chromosome condensation during mitotic cell division. A strong correlation between the initial chromosome condensation and histone H3 phosphorylation has been observed in mammalian cells, and its phosphorylation at Ser10 has been suggested to play a key role in mitotic chromosome condensation. The spatiotemporal distribution of histone H3 phosphorylation is different among the cell types so far examined. However, there is no evidence about histone H3 phosphorylation in meiotic chromosome condensation in mammalian oocytes.

Both Ipl1/aurora-B kinase and its genetically interacting protein phosphatase Glc7/PP1 has been shown to be required for H3 phosphorylation during mitosis in Saccha-romyces cerevisiae and Caenorhabditis elegans. It is suggested in somatic cells that the balance of histone H3 kinase and PP1 acting on Ser10 of histone H3 regulates chromosome condensation. Inhibitors of the protein serine/ threonine phosphatases PP1 and PP2A, such as okadaic acid (OA) and calyculin A (CL-A), induce rapid chromosome condensation in oocytes. However, it remains to be elucidated whether the effect of PP1/PP2A inhibitors on the chromosome condensation correlates with Cdc2 kinase, MAP kinase, or histone H3 kinase.

In this study, we investigated the changes in histone H3 phosphorylation at Ser10 during meiotic maturation and rapid chromosome condensation induced by the inhibition of PP1/PP2A in pig oocytes. Histone H3 phosphorylation was detected in the clump of condensed chromosomes at the diakinesis stage and maintained during maturation of the oocytes. Histone H3 was also phosphorylated in condensed chromosomes in the inhibitor-treated oocytes. Furthermore, the chromosome condensation occurred without GVBD in the absence of the activation of both Cdc2 kinase and MAP kinase but was accompanied by histone H3 kinase activation.

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