Phosphorylation of Bcl-2 Protein by CDC2 Kinase during G2/M Phases and Its Role in Cell Cycle Regulation

Furukawa, Yusuke; Iwase, Satsuki; Kikuchi, Jiro; Terui, Yasuhito; Nakamura, Mitsuru; Yamada, Hisashi; Kano, Yasuhiko; Matsuda, Michio

doi:10.1074/jbc.m906893199

Cited by 106 publications

(91 citation statements)

References 40 publications

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“…Our observation of signi®cantly reduced oocyte maturation as a result of Bcl-2 overexpression is consistent with the ®nding of Bcl-2-dependent accumulation of cells in the human promyelocytic leukemia cell line HL-60 in the G2/M phases of the eukaryotic cell cycle (Furukawa et al, 2000). In the latter study, the cell cycle inhibitory e ect of Bcl-2 was attributed to Bcl-2 phosphorylation by CDC2 kinase.…”

Section: Discussionsupporting

confidence: 76%

“…Recently reported evidence supports the existence of a Bcl-2-sensitive communication between the ER and mitochondria that involves Ca 2+ and may a ect sensitivity to apoptosis Hacki et al, 2000). In addition to its anti-apoptotic function, Bcl-2 has been implicated in the regulation of cell cycle progression at both the G1 to S transition (Vairo et al, 1996) and the G2/M phases of the mitotic cell cycle (Furukawa et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Evidence for a role of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in thapsigargin and Bcl-2 induced changes in Xenopus laevis oocyte maturation

Kobrinsky

Kirchberger

2001

Oncogene

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Thapsigargin (Tg), a selective inhibitor of sarcoplasmic/ endoplasmic reticulum Ca 2+ -ATPase (SERCA), causes depletion of intracellular Ca 2+ stores, hence activation of capacitative Ca 2+ entry (CCE). Incubation of Xenopus laevis oocytes with Tg resulted in an increased rate of progesterone-induced meiotic maturation. Non-mitochondrial 45 Ca 2+ uptake by SERCA-containing microsomes prepared from control wild-type oocytes microinjected with sterile water was inhibited essentially 100% by Tg. However, overexpression of Bcl-2, an oncogene known to protect against Tg-induced apoptosis in certain cell types, resulted in only 40% inhibition of microsomal 45 Ca 2+ uptake by Tg while non-inhibited 45 Ca 2+ uptake remained unchanged. Moreover Bcl-2 overexpression also protected against inhibition of CCE. I Cl(Ca) was similar in Bcl-2-overexpressing and control oocytes when intracellular Ca 2+ store depletion was induced by microinjection of inositol 1,4,5-trisphosphate (InsP 3 ) and other means and when CCE was induced by means independent of SERCA inhibition. Our data indicate that Bcl-2 a ects neither the InsP 3 receptor nor Ca 2+ entry itself. At the end of a 24-h period after progesterone addition to the medium, only 25% of Bcl-2-overexpressing oocytes had matured compared to 85% of control oocytes. Our data suggest that SERCA participates in Xenopus oocyte maturation by controlling cytosolic Ca 2+ and/or intracellular Ca 2+ stores, hence CCE. An observed progesterone-dependent protein kinase-catalysed phosphorylation of SERCA is further indication of its role in oocyte maturation. Oncogene (2001) 20, 933 ± 941.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Evidence for a role of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in thapsigargin and Bcl-2 induced changes in Xenopus laevis oocyte maturation

Kobrinsky

Kirchberger

2001

Oncogene

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“…We simultaneously measured cellular content of Bcl-2 family proteins and DNA content in AML cells under unstressed conditions and found that the expression of Bcl-2 peaks in G 2 /M-phase where phosphorylation of Bcl-2 at Ser 70 occurs. 31 Interestingly, Bcl-2 levels increased during G 1 to G 2 progression and the amplitude of Bcl-2 change was larger than that of Bax, suggesting that the cellular Bcl-2/Bax ratio is lowest in G 1 cells. It has been described that, in chronic lymphocytic leukemia cells, decreased Bcl-2/Bax ratios and conformational changes of Bax and Bak are among the early steps of spontaneous apoptosis initiation.…”

Section: Discussionmentioning

confidence: 99%

“…High levels of Bcl-2 and its phosphorylation are associated with resistance to ABT-737-induced apoptosis in AML (unpublished results), 12 and phosphorylated Bcl-2 has been described to be expressed during G 2 /M-phase. 30,31 It is therefore possible that Bcl-2 levels may change during cell cycle progression and that the relative expression levels may be associated with susceptibility to spontaneous and Bcl-2 inhibitor-induced apoptosis. To address this issue, the cellular content of apoptosis-associated proteins was measured in conjunction with DNA content in unstressed OCI-AML-3 cells.…”

Section: Resultsmentioning

confidence: 99%

Concomitant Inhibition of MDM2 and Bcl-2 Protein Function Synergistically Induce Mitochondrial Apoptosis in AML

Kojima¹,

Konopleva²,

Samudio³

et al. 2006

Cell Cycle

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Disruption of Mdm2-p53 interaction activates p53 signaling, disrupts the balance of antiapoptotic and proapoptotic Bcl-2 family proteins and induces apoptosis in acute myeloid leukemia (AML). Overexpression of Bcl-2 may inhibit this effect. Thus, functional inactivation of antiapoptotic Bcl-2 proteins may enhance apoptogenic effects of Mdm2 inhibition. We here investigate the potential therapeutic utility of combined targeting of Mdm2 by Nutlin-3a and Bcl-2 by ABT-737, recently developed inhibitors of protein-protein interactions. Nutlin-3a and ABT-737 induced Bax conformational change and mitochondrial apoptosis in AML cells in a strikingly synergistic fashion. Nutlin-3a induced p53-mediated apoptosis predominantly in S and G 2 /M cells, while cells in G 1 were protected through induction of p21. In contrast, ABT-737 induced apoptosis predominantly in G 1 , the cell cycle phase with the lowest Bcl-2 protein levels and Bcl-2/ Bax ratios. In addition, Bcl-2 phosphorylation on Ser 70 was absent in G 1 but detectable in G 2 /M, thus lower Bcl-2 levels and absence of Bcl-2 phosphorylation appeared to facilitate ABT-737-induced apoptosis of G 1 cells. The complementary effects of Nutlin-3a and ABT-737 in different cell cycle phases could, in part, account for their synergistic activity. Our data suggest that combined targeting of Mdm2 and Bcl-2 proteins could offer considerable therapeutic promise in AML.

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“…2A). Bcl-2, an anti-apoptotic protein that is phosphorylated and inactivated by Cdk2 kinase during the G2/M transition in proliferating cells (Furukawa et al, 2000), was dephosphorylated and, hence, activated during C2C12 cell differentiation ( Fig. 2A).…”

Section: Model For Cell Cycle Withdrawal In C2c12 Myoblastsmentioning

confidence: 99%

Genome‐wide examination of myoblast cell cycle withdrawal during differentiation

Shen

Collier

Hlaing

et al. 2002

Developmental Dynamics

107

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Skeletal and cardiac myocytes cease division within weeks of birth. Although skeletal muscle retains limited capacity for regeneration through recruitment of satellite cells, resident populations of adult myocardial stem cells have not been identified. Because cell cycle withdrawal accompanies myocyte differentiation, we hypothesized that C2C12 cells, a mouse myoblast cell line previously used to characterize myocyte differentiation, also would provide a model for studying cell cycle withdrawal during differentiation. C2C12 cells were differentiated in culture medium containing horse serum and harvested at various time points to characterize the expression profiles of known cell cycle and myogenic regulatory factors by immunoblot analysis. BrdU incorporation decreased dramatically in confluent cultures 48 hr after addition of horse serum, as cells started to form myotubes. This finding was preceded by up-regulation of MyoD, followed by myogenin, and activation of Bcl-2. Cyclin D1 was expressed in proliferating cultures and became undetectable in cultures containing 40% fused myotubes, as levels of p21 WAF1/Cip1 increased and ␣-actin became detectable. Because C2C12 myoblasts withdraw from the cell cycle during myocyte differentiation following a course that recapitulates this process in vivo, we performed a genome-wide screen to identify other gene products involved in this process. Using microarrays containing ϳ10,000 minimally redundant mouse sequences that map to the UniGene database of the National Center for Biotechnology Information, we compared gene expression profiles between proliferating, differentiating, and differentiated C2C12 cells and verified candidate genes demonstrating differential expression by RT-PCR. Cluster analysis of differentially expressed genes revealed groups of gene products involved in cell cycle withdrawal, muscle differentiation, and apoptosis. In addition, we identified several genes, including DDAH2 and Ly-6A, whose expression specifically was up-regulated during cell cycle withdrawal coincident with early myoblast differentiation. Developmental Dynamics 226:128 -138, 2003.

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Phosphorylation of Bcl-2 Protein by CDC2 Kinase during G2/M Phases and Its Role in Cell Cycle Regulation

Cited by 106 publications

References 40 publications

Evidence for a role of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in thapsigargin and Bcl-2 induced changes in Xenopus laevis oocyte maturation

Evidence for a role of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in thapsigargin and Bcl-2 induced changes in Xenopus laevis oocyte maturation

Concomitant Inhibition of MDM2 and Bcl-2 Protein Function Synergistically Induce Mitochondrial Apoptosis in AML

Genome‐wide examination of myoblast cell cycle withdrawal during differentiation

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