Cell Cycle-Specific Changes in Histone Phosphorylation Associated With Cell Proliferation and Chromosome Condensation

Abstract

Preparative polyacrylamide gel electrophoresis was used to examine histone phosphorylation in synchronized Chinese hamster cells (line CHO) . Results showed that histone fl phosphorylation, absent in GI-arrested and early GI-traversing cells, commences 2 h before entry of traversing cells into the S phase . It is concluded that fl phosphorylation is one of the earliest biochemical events associated with conversion of nonproliferating cells to proliferating cells occurring on old fi before synthesis of new fl during the S phase . Results also showed that f3 and a subfraction of fl were rapidly phosphorylated only during the time when cells were crossing the G 2/M boundary and traversing prophase .Since these phosphorylation events do not occur in G I , S, or G 2 and are reduced greatly in metaphase, it is concluded that these two specific phosphorylation events are involved with condensation of interphase chromatin into mitotic chromosomes . This conclusion is supported by loss of prelabeled 32 P04 from those specific histone fractions during transition of metaphase cells into interphase G, cells . A model of the relationship of histone phosphorylation to the cell cycle is presented which suggests involvement of fi phosphorylation in chromatin structural changes associated with a continuous interphase "chromosome cycle" which culminates at mitosis with an f3 and fl phosphorylation-mediated chromosome condensation .

Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts

“…15) and pHH3 (G 2 -M phase; ref. 16), as two additional transit compartments downstream of p-Rb. As p-Rb can also be used as a phenotypic biomarker for late G 1 -phase (6,7), this extended PD model can be regarded as a simplified integrated cell-cycle model.…”

“…1) was developed using colo-205 xenograft tumor data and is composed of four transit compartments, each corresponding to early G 1 , late G 1 , S, and G 2 -M cell-cycle phases in a sequential, open-loop manner. The biomarkers, p-Rb, TopoIIa, and pHH3, were used to represent the change in cell phase density in late G 1 , S, and G 2 -M phases, respectively (6,7,15,16). As the formation of p-Rb occurs at the G 1 restriction point, the drug effect was implemented on the transition between early and late G 1 -phase.…”

Changes in chromatin and the phosphorylation of nuclear proteins during heat shock of Achlya ambisexualis.

“…In CHO cells both histones Hi and H3 become rapidly phosphorylated at the time cells cross the G2/M boundary of the cell cycle (13,14). Histone phosphorylation is thought to be involved in either the mechanism which triggers the chromosomes to condense or the maintenance of the mitotic chromatin in the condensed form.…”

“…In higher eucaryotes and also in the slime mold Physarum polycephalum, the phosphorylation of histone H3 and histone Hi is associated with the condensation of chromatin during mitosis (3,7,13,14). The apparent phosphorylation of Achlya histones during heat shock was therefore of particular interest to us, since Achlya nuclei normally contain no discernible heterochromatin and Achlya chromosomes like those of the related water mold Saprolegnia ferax (15) are not thought to condense even when cells are undergoing mitosis.…”

Effects of two mercuric water pollutants on growth and cell division of Hydrilla verticillata.

“…Condensation of the interphase chromosome into mitotic chromosome involved two specific phosphorylation events (Gurley et al 1974) in synchronised chinese hamster cell cul ture. It was observed that subfraction of HI and histone of H3 (Arginine-rich) were rapidly phosphorylated when cells were passing through G2/M boundary and going to prophase.…”