Hematopoiesis specific loss of Cdk2 and Cdk4 results in increased erythrocyte size and delayed platelet recovery following stress

Jayapal, Senthil Raja; Wang, Chelsia Qiuxia; Bisteau, Xavier; Caldez, Matias J.; Lim, Shuhui; Tergaonkar, Vinay; Osato, Motomi; Kaldis, Philipp

doi:10.3324/haematol.2014.106468

Cited by 26 publications

(23 citation statements)

References 31 publications

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“…Notably, no evident abnormalities were observed in HSCs from CDK2-deficient mice, indicating that other molecules (such as the CDK1-cyclin E complex as reasoned in the following section) may compensate for the loss of CDK2 [25]. Although mice lacking either CDK2 or CDK4 are viable, double knockout mutants for these two molecules are embryonically lethal at around E15 due to heart defects, indicating that CDK2 and CDK4 play synergistic roles during development [24,26].…”

Section: Cdk2mentioning

confidence: 96%

“…CDK2-deficient mice are viable and have a life span of more than 2 years, suggesting that CDK2 is dispensable for the proliferation and survival of most somatic cell types. However, while CDK2 mutant mice are overtly normal, they are sterile, as CDK2 has been shown to be essential for the completion of prophase I during meiotic cell division in male germ cells [24]. Notably, no evident abnormalities were observed in HSCs from CDK2-deficient mice, indicating that other molecules (such as the CDK1-cyclin E complex as reasoned in the following section) may compensate for the loss of CDK2 [25].…”

Section: Cdk2mentioning

confidence: 98%

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Cell cycle regulation of hematopoietic stem or progenitor cells

2016

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Section: Cdk2mentioning

confidence: 96%

Section: Cdk2mentioning

confidence: 98%

Cell cycle regulation of hematopoietic stem or progenitor cells

2016

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“…34 Consistent with this theory, several cell cycle proteins that control the G1-S transition, such as E2F4, [35][36][37] Cdk4/Cdk6, 2 cyclin D3, 38 and Cdk2/Cdk4, 20 play critical roles in the regulation of erythrocyte size and numbers. Erythroblasts lacking cyclin D3 underwent reduced number of cell divisions during terminal differentiation resulting in a dramatic 40% increase in erythrocyte MCV and 38% decrease in erythrocyte counts in the peripheral blood of cyclin D3 ¡/¡ mice.…”

Section: Discussionmentioning

confidence: 92%

Cyclin A2 regulates erythrocyte morphology and numbers

et al. 2016

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Cyclin A2 is an essential gene for development and in haematopoietic stem cells and therefore its functions in definitive erythropoiesis have not been investigated. We have ablated cyclin A2 in committed erythroid progenitors in vivo using erythropoietin receptor promoter-driven Cre, which revealed its critical role in regulating erythrocyte morphology and numbers. Erythroid-specific cyclin A2 knockout mice are viable but displayed increased mean erythrocyte volume and reduced erythrocyte counts, as well as increased frequency of erythrocytes containing Howell-Jolly bodies. Erythroblasts lacking cyclin A2 displayed defective enucleation, resulting in reduced production of enucleated erythrocytes and increased frequencies of erythrocytes containing nuclear remnants. Deletion of the Cdk inhibitor p27 Kip1 but not Cdk2, ameliorated the erythroid defects resulting from deficiency of cyclin A2, confirming the critical role of cyclin A2/Cdk activity in erythroid development. Loss of cyclin A2 in bone marrow cells in semisolid culture prevented the formation of BFU-E but not CFU-E colonies, uncovering its essential role in BFU-E function. Our data unveils the critical functions of cyclin A2 in regulating mammalian erythropoiesis.

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“…Recently, hematopoiesis was shown to be affected in mice with a combined deficiency of CDK2 and CDK4 [18]. Interestingly, the combined deficiency of these cyclin-dependent kinases resulted in increased erythrocyte cell volume [18].…”

Section: +mentioning

confidence: 99%

“…Interestingly, the combined deficiency of these cyclin-dependent kinases resulted in increased erythrocyte cell volume [18]. The CDK4 inhibitors used in this study are chemically unrelated compounds which have previously been shown to potently inhibit CDK4 kinase activity.…”

Section: +mentioning

confidence: 99%

Impact of Cyclin-Dependent Kinase CDK4 Inhibition on Eryptosis

Lang

Zelenak

Eberhard

et al. 2015

Cell Physiol Biochem

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Background/Aims: The cyclin-dependent kinase 4 (CDK4) participates in the regulation of apoptosis of nucleated cells by altering transcriptional regulation of genes governing cell proliferation and cell death. Similar to apoptosis of nucleated cells, erythrocytes may enter eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine (PS) exposure at the cell surface. As mature erythrocytes lack nuclei, acute stimulation of eryptosis cannot result from altered gene expression. Eryptosis is triggered by isotonic cell shrinkage following Cl^- removal (replacement with the impermeant organic anion gluconate) or by oxidative stress (exposure to 0.3 mM tertbutyl-hydroperoxide [tBOOH]). The present study explored whether CDK4 is expressed in erythrocytes and whether the CDK4 inhibitors II (NSC625987) and III (ryuvidine) influence eryptosis. Methods: Western blotting was utilized for determination of the presence of CDK4 protein in human erythrocytes, and FACS analysis to determine Fluo3 fluorescence (reflecting cytosolic Ca²⁺), annexin-V-binding (reflecting PS-exposure) and forward scatter (reflecting cell volume). Results: CDK4 protein was present in human erythrocytes. Cl^- removal was followed by decrease of forward scatter and increase of both annexin-V-binding and Fluo3 fluorescence, an effect significantly curtailed by CDK4 inhibitors II and III. Furthermore, CDK4 inhibition blunted enhanced PS-exposure elicited by tBOOH treatment. Conclusions: The present observations disclose the presence of CDK4 protein in human erythrocytes and the suppression of suicidal erythrocyte death by pharmacological inhibition of CDK4.

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Hematopoiesis specific loss of Cdk2 and Cdk4 results in increased erythrocyte size and delayed platelet recovery following stress

Abstract: ABSTRACTcrossed with Cdk4 +/-mice, 10 and the resulting heterozygous offspring Cdk2 +/fl

Cited by 26 publications

References 31 publications

Cell cycle regulation of hematopoietic stem or progenitor cells

Cell cycle regulation of hematopoietic stem or progenitor cells

Cyclin A2 regulates erythrocyte morphology and numbers

Impact of Cyclin-Dependent Kinase CDK4 Inhibition on Eryptosis

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