Involvement of RB kinases and phosphatases in life and death decisions

An, Bing; Dineley, Kirk E.; Zhang, L; Termin, Toni A; Meijer, L.; Dou, Q. Ping

doi:10.3892/or.4.6.1129

Cited by 4 publications

(3 citation statements)

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“…A genetic study in Drosophila melanogaster revealed normal regulation of Rb ⁄ E2F1 target genes in mutant flies in which all PP1 C encoding genes were inactivated, suggesting that, in this organism, either another phosphatase is involved in the dephosphorylation of Rb or that it acts redundantly with PP1 [80]. Indeed, it was observed that when CDK activity was inhibited by addition of roscovitine, a potent and selective inhibitor of CDK1, CDK2 and CDK5, Rb dephosphorylation was rapidly induced in Jurkat cells, and this was blocked by CalA or OA [81]. Thus, it was concluded that Rb phosphorylation might in part be determined by a balance between CDK kinases and PP1 ⁄ PP2A.…”

Section: The Role Of Pp2a In Rb Dephosphorylation During the Cell Cyclementioning

confidence: 99%

PP1 and PP2A phosphatases – cooperating partners in modulating retinoblastoma protein activation

Kolupaeva

Janssens

2012

The FEBS Journal

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The retinoblastoma ⁄ pocket protein family is one of the master regulators of the eukaryotic cell cycle. It includes the retinoblastoma protein (Rb) and the related p107 and p130 proteins. The importance of the Rb pathway for homeostasis and tumour suppression is evident from the fact that inactivating mutations in Rb are frequently associated with many cancers. Rbs regulate the cell cycle by controlling the activity of the E2F family of transcription factors. The activity of Rb proteins themselves is modulated by their phosphorylation status at several Ser ⁄ Thr residues: phosphorylation by cyclin-dependent kinases inactivates Rb proteins and positively influences the transcription of genes necessary for cell cycle progression. Although the mechanisms of cyclin-dependent kinase-mediated inactivation of Rb proteins are understood in great detail, our knowledge of the process that counteracts Rb phosphorylation is still quite limited. The present review focuses on the Ser ⁄ Thr phosphatases that are responsible for the dephosphorylation and thus activation of Rb proteins. Two major scenarios are considered: (a) when pocket proteins are dephosphorylated during regular cell cycle progression and (b) when rapid dephosphorylation is dictated by external stress or growth inhibitory conditions, such as oxidative stress, UV radiation or other DNA-damaging stimuli, and cell differentiation factors. It transpires that protein phosphatase 1 and protein phosphatase 2A can efficiently modulate pocket protein activity in a highly context-dependent manner and both are tightly regulated by the presence of different regulatory subunits or interacting proteins.

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Section: The Role Of Pp2a In Rb Dephosphorylation During the Cell Cyclementioning

confidence: 99%

PP1 and PP2A phosphatases – cooperating partners in modulating retinoblastoma protein activation

Kolupaeva

Janssens

2012

The FEBS Journal

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“…74 The notion that the phosphorylation state of pRB could be determined by the ratio of pRB kinases and phosphatases has also been proposed. 75 More recently, it has been shown that PP2A/PR70 holoenzymes target pRB for Tumor suppressors in the network are inactivated via point mutations or deletions (X) or via epigenetic silencing or increased proteolytic degradation (↓). Mutations and or deletions affecting pRB, p130, and p16 have been described (reviewed in Malumbres & Barbacid 94 ).…”

Section: Alterations On B55a May Be Linked To Inactivation Of the Pocmentioning

confidence: 99%

“…74 The notion that the phosphorylation state of pRB could be determined by the ratio of pRB kinases and phosphatases has also been proposed. 75…”

Section: Alterations On B55α May Be Linked To Inactivation Of the Pocmentioning

confidence: 99%

PP2A Counterbalances Phosphorylation of pRB and Mitotic Proteins by Multiple CDKs: Potential Implications for PP2A Disruption in Cancer

Kurimchak¹,

Graña²

2012

Genes & Cancer

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Protein Phosphatase 2A (PP2A) consists of a collection of heterotrimeric serine/threonine phosphatase holoenzymes that play multiple roles in cell signaling via dephosphorylation of numerous substrates of a large family of serine/threonine kinases. PP2A substrate specificity is mediated by B regulatory subunits of four different families, which selectively recognize diverse substrates by mechanisms that are not well understood. Among the many signaling pathways with critical PP2A functions are several deregulated in cancer cells, and PP2A is a know tumor suppressor. However, the precise composition of the heterotrimeric PP2A complexes with tumor supressor activity is not well understood. This review is centered on the emerging role of the B regulatory subunit B55a and related subfamilly members in the modulation of the phosphorylation state of pocket proteins and mitotic CDK substrates, as well as the implications of PP2A function disruption in cancer in the context of these activities.

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Properties and Potential Applications of Chemical Inhibitors of Cyclin-Dependent Kinases

Meijer

Leclerc

Leost

1999

Pharmacology & Therapeutics

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Involvement of RB kinases and phosphatases in life and death decisions

Cited by 4 publications

References 0 publications

PP1 and PP2A phosphatases – cooperating partners in modulating retinoblastoma protein activation

PP1 and PP2A phosphatases – cooperating partners in modulating retinoblastoma protein activation

PP2A Counterbalances Phosphorylation of pRB and Mitotic Proteins by Multiple CDKs: Potential Implications for PP2A Disruption in Cancer

Properties and Potential Applications of Chemical Inhibitors of Cyclin-Dependent Kinases

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