Positive Regulation of cdc2 Gene Activity by Protein Phosphatase Type 2A

Jaramillo-Babb, Virna L.; Sugarman, Jeffrey; Scavetta, Robert D.; Wang, Shiow-Jen; Berndt, Norbert; Born, Teresa L.; Glass, Christopher K.; Schönthal, Axel H.

doi:10.1074/jbc.271.11.5988

Cited by 21 publications

(22 citation statements)

References 29 publications

(32 reference statements)

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“…Our results are consistent with previous studies in NIH 3T3 cells showing that okadaic acid causes a G 1 arrest that correlates with decreased pRB phosphorylation, decreased CDK activity, and a block in cyclin A, CDC2, and CDK2 expression (31). Consistent with a role in transcriptional regulation of CDC2, transient expression of the PP2A catalytic subunit can positively regulate CDC2 gene expression (54). However, the effects of OA may depend on the cell type as OA caused induction rather than repression of cyclin A, cyclin B, and CDC2 in transformed cells (55).…”

Section: Discussionmentioning

confidence: 81%

Distinct Roles for PP1 and PP2A in Phosphorylation of the Retinoblastoma Protein

Yan

Mumby

1999

Journal of Biological Chemistry

108

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The retinoblastoma tumor suppressor gene encodes a nuclear phosphoprotein (pRB) 1 that regulates the G 1 /S transition of the cell cycle. The active form of pRB binds and inactivates transcription factors, including members of the E2F family, whose target genes are necessary for S phase (1-3). The activity of pRB is regulated by phosphorylation and dephosphorylation of serine and threonine residues. pRB is dephosphorylated during mitosis, and the active, hypophosphorylated form inhibits cell cycle progression during early and mid G 1 (4). pRB accumulates in the inactive, hyperphosphorylated state in late G 1 and phosphorylation is maintained during S and G 2 . Hyperphosphorylation causes dissociation of pRB from E2F, induction of gene transcription, and progression into S phase (5). Because of its central role in progression through G 1 , pRB serves as an important point of integration for numerous signaling pathways that influence the cell cycle (2).pRB is phosphorylated by members of the cyclin-dependent family of serine/threonine kinases whose active forms consist of a catalytic subunit (CDK) complexed with a cyclin partner (2, 3). The major kinases that phosphorylate pRB during G 1 include cyclin E-CDK2, cyclin D-CDK4, and cyclin D-CDK6. pRB phosphorylation is initiated in a growth factor-dependent manner by assembly of cyclin D with CDK4. Phosphorylation is then accelerated during late G 1 by cyclin E-CDK2 (6). Maintenance of the phosphorylated state during S and G 2 is due to the actions of cyclin A-and cyclin B-CDK complexes. Cyclin-CDK complexes phosphorylate multiple proline-directed consensus sites on pRB (7). The activities of G 1 CDKs are regulated not only by the availability of cyclins, but also by activating (8) and inhibitory (9, 10) phosphorylation of the CDK catalytic subunit. CDK activity is down-regulated by cyclin-dependent kinase inhibitors. Inhibitors of G 1 CDKs include p21 Cip1 , p27 Kip1 , and p57Kip2 . Cyclin D-CDKs are also inhibited by a set of specific CDK inhibitors termed INK4 proteins (11-13).pRB is reactivated by dephosphorylation at the end of mitosis. Protein phosphatase 1 has been implicated as the major pRB phosphatase in vivo. Dephosphorylation of pRB by PP1 is thought to play a critical role in controlling the G 1 /S transition (14). The phosphorylation state (15) and activity (16, 17) of PP1 vary during the cell cycle. Dephosphorylation of pRB by mitotic cell extracts is sensitive to inhibitors of PP1 (16), and a high molecular weight form of PP1 has been isolated as a pRB phosphatase (18). pRB can associate with the catalytic subunit of PP1 (19), and a constitutively active form of PP1 induces dephosphorylation of pRB and pRB-dependent cell cycle arrest (20).Protein phosphatase 2A has been implicated in the regulation of many cellular functions including the cell cycle (21-23). Studies in Xenopus extracts (24) and fission yeast (25,26) have demonstrated that PP2A plays a role in the G 2 to M transition. The G 2 /M function of PP2A is likely to involve regulation of th...

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Section: Discussionmentioning

confidence: 81%

Distinct Roles for PP1 and PP2A in Phosphorylation of the Retinoblastoma Protein

Yan

Mumby

1999

Journal of Biological Chemistry

108

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“…5B). In order to specifically examine the role of PP2A, we used okadaic acid (OA) and endothall, which are preferential inhibitors of this enzyme (10,22,26). We found that treatment of CH12 B cells with 300 nM okadaic acid or 50 M endothall led to phosphatase inhibition as measured by Western blotting with antiphosphoserine antibodies, as well as increased AID-S3 phosphorylation (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…However, PP2A appears to be a key regulator of the level of AID phosphorylation at S3, since defined pharmacological PP2A inhibitors augment AID-S3 phosphorylation in vivo. Calyculin inhibits both PP2A and PP1 equally (50% inhibitory concentration [IC 50 ], 1 nM), okadaic acid has a Ͼ100-fold-higher affinity for PP2A (IC 50 , 1 nM) (10,22), and endothall is a PP2A-specific inhibitor (26). Each of these inhibitors augments AID-S3 phosphorylation in stimulated B cells and also inhibits CSR (Fig.…”

Section: Discussionmentioning

confidence: 99%

Amino-Terminal Phosphorylation of Activation-Induced Cytidine Deaminase Suppresses c-myc/IgH Translocation

Gazumyan

Timachova

Yuen

et al. 2011

Molecular and Cellular Biology

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Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates class switch recombination and somatic hypermutation of immunoglobulin genes (Ig) in B lymphocytes. However, AID also produces off-target DNA damage, including mutations in oncogenes and double-stranded breaks that can serve as substrates for oncogenic chromosomal translocations. AID is strictly regulated by a number of mechanisms, including phosphorylation at serine 38 and threonine 140, which increase activity. Here we show that phosphorylation can also suppress AID activity in vivo. Serine 3 is a novel phospho-acceptor which, when mutated to alanine, leads to increased class switching and c-myc/IgH translocations without affecting AID levels or catalytic activity. Conversely, increasing AID phosphorylation specifically on serine 3 by interfering with serine/threonine protein phosphatase 2A (PP2A) leads to decreased class switching. We conclude that AID activity and its oncogenic potential can be downregulated by phosphorylation of serine 3 and that this process is controlled by PP2A.

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“…Cell Culture and Transfection-Mouse NIH3T3 and human HeLa cells were grown in 10% calf serum/Dulbecco's modified Eagle's medium as described (25). Transfections were performed in 6-cm tissue culture dishes using the calcium-phosphate-DNA precipitation technique.…”

Section: Methodsmentioning

confidence: 99%

Autoregulation of Protein Phosphatase Type 2A Expression

Baharians

Schönthal

1998

Journal of Biological Chemistry

Self Cite

138

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Protein phosphatases are involved in many cellular processes. One of the most abundant of these enzymes, the serine/threonine-specific protein phosphatase type 2A (PP2A), is present in most eukaryotic cells and serves a variety of functions. However, the detailed study of its regulation and function has been hampered by the difficulty of manipulating its expression level in cell culture. By using a new mammalian expression vector to forcibly overexpress PP2A in the mouse fibroblast cell line NIH3T3, we now show that the catalytic subunit of PP2A is subject to a potent autoregulatory mechanism that adjusts PP2A protein to constant levels. This control is exerted at the translational level and does not involve regulation of transcription or RNA processing. Thus, our results demonstrate tight control of PP2A expression, and provide an explanation for the difficulty of increasing PP2A expression experimentally.

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Positive Regulation of cdc2 Gene Activity by Protein Phosphatase Type 2A

Cited by 21 publications

References 29 publications

Distinct Roles for PP1 and PP2A in Phosphorylation of the Retinoblastoma Protein

Distinct Roles for PP1 and PP2A in Phosphorylation of the Retinoblastoma Protein

Amino-Terminal Phosphorylation of Activation-Induced Cytidine Deaminase Suppresses c-myc/IgH Translocation

Autoregulation of Protein Phosphatase Type 2A Expression

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