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J Biol Chem. 2010 Jul 9;285(28):21567-80. doi: 10.1074/jbc.M109.094953. Epub 2010 May 6.

The B56gamma3 regulatory subunit of protein phosphatase 2A (PP2A) regulates S phase-specific nuclear accumulation of PP2A and the G1 to S transition.

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Institute of Basic Medical Sciences, Cheng Kung University, Tainan 701, Taiwan.


Protein phosphatase 2A (PP2A) is a heterotrimeric enzyme consisting of a scaffold subunit (A), a catalytic subunit (C), and a variable regulatory subunit (B). The regulatory B subunits determine the substrate specificity and subcellular localization of the PP2A holoenzyme. Here, we demonstrate that the subcellular localization of the B56gamma3 regulatory subunit is regulated in a cell cycle-specific manner. Notably, B56gamma3 becomes enriched in the nucleus at the G(1)/S border and in S phase. The S phase-specific nuclear enrichment of B56gamma3 is accompanied by increases of nuclear A and C subunits and nuclear PP2A activity. Overexpression of B56gamma3 promotes nuclear localization of the A and C subunits, whereas silencing both B56gamma2 and B56gamma3 blocks the S phase-specific increase in the nuclear localization and activity of PP2A. In NIH3T3 cells, B56gamma3 overexpression reduces p27 phosphorylation at Thr-187, concomitantly elevates p27 protein levels, delays the G(1) to S transition, and retards cell proliferation. Consistently, knockdown of endogenous B56gamma3 expression reduces p27 protein levels and increases cell proliferation in HeLa cells. These findings demonstrate that the dynamic nuclear distribution of the B56gamma3 regulatory subunit controls nuclear PP2A activity, which regulates cell cycle controllers, such as p27, to restrain cell cycle progression, and may be responsible for the tumor suppressor function of PP2A.

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