Cdk6 contributes to cytoskeletal stability in erythroid cells

Abstract

Mice lacking Cdk6 kinase activity suffer from mild anemia accompanied by elevated numbers of Ter119+ cells in the bone marrow. The animals show hardly any alterations in erythroid development, indicating that Cdk6 is not required for proliferation and maturation of erythroid cells. There is also no difference in stress erythropoiesis following hemolysis in vivo. However, Cdk6−/− erythrocytes have a shortened lifespan and are more sensitive to mechanical stress in vitro, suggesting differences in cytoskeletal architecture. Erythroblasts contain both Cdk4 and Cdk6, while mature erythrocytes apparently lack Cdk4 and their Cdk6 is partly associated with the cytoskeleton. We used mass spectrometry to show that Cdk6 interacts with a number of proteins involved in cytoskeleton organization. Cdk6−/− erythroblasts show impaired F-actin formation and lower levels of gelsolin, which interacts with Cdk6. We also found that Cdk6 regulates the transcription of a panel of genes involved in actin (de-)polymerization. Cdk6-deficient cells are sensitive to drugs that interfere with the cytoskeleton, suggesting that our findings are relevant to the treatment of patients with anemia – and may be relevant to cancer patients treated with the new generation of CDK6 inhibitors.

CDK6 Inhibition: A Novel Approach in AML Management

“…The simultaneous deletion of both CDKs induces late embryonic lethality in mice due to defects in hematopoiesis [6,7]. Loss of Cdk6 alone is compatible with life but leads to defects in hematopoietic cell proliferation and mild anemia [7,8]. There is increasing evidence for additional substrates and functional differences between these two kinases that go beyond the control of cell cycle [9] (Figure 1).…”

“…Contrary to CDK4, the CDK6 gene is frequently amplified or overexpressed in a variety of human lymphomas and leukemias [7,[10][11][12][13][14][15][16][17][18][19][20][21]. During the last years, it has been shown that CDK6 but not CDK4 is a direct regulator of transcription in a kinase-dependent and -independent manner, interacting with a range of transcription factors including members of the signal transducer and activator of transcription (STAT) and activator protein 1 (AP-1) family [8,[22][23][24][25][26][27]. Besides inducing the transcription of the tumor suppressor p16 INK4A as an endogenous feed-back loop, CDK6 also mediates the transcription of vascular endothelial growth factor A (VEGF-A), a well-characterized angiogenic factor and tumor promoter, thereby linking two hallmark cancer features [28,29].…”

“…Besides inducing the transcription of the tumor suppressor p16 INK4A as an endogenous feed-back loop, CDK6 also mediates the transcription of vascular endothelial growth factor A (VEGF-A), a well-characterized angiogenic factor and tumor promoter, thereby linking two hallmark cancer features [28,29]. In addition, CDK6 stabilizes the cytoskeletal integrity of erythroid cells on a transcriptional and structural level [8] (Figure 1). in hematopoiesis [6,7].…”

Whole-Genome Methylation Analysis Reveals Epigenetic Variation in Cloned and Donor Pigs

“…Cyclin-dependent kinase, CDK6, is a driving factor for cell proliferation and can bind D cell cycle protein 3 to promote tumor cell apoptosis . A lack of CDK6 usually leads to anemia, while overexpression leads to hematologic malignancies (Kollmann et al, 2016;Uras et al, 2017). Most of the aforementioned DMGs were enriched in cancer, T/B, NK cell differentiation, and other immune pathways, which are important for the prevention and development of disease (Kaur et al, 2013;Kuwabara et al, 2018;Mazzone et al, 2019).…”

Normal and pathological erythropoiesis in adults: from gene regulation to targeted treatment concepts

“…One of these regulators may be CDK6, a cell cycle regulator that has recently been shown to serve as a membrane stabilizer of red cells in mice. 49 …”