A ROS-dependent mechanism promotes CDK2 phosphorylation to drive progression through S phase

Kirova, Dilyana Georgieva; Judasová, Kristýna; Vorhauser, Julia; Zerjatke, Thomas; Leung, Jacky K.; Glauche, Ingmar; Mansfeld, Jörg

doi:10.1016/j.devcel.2022.06.008

Cited by 66 publications

(40 citation statements)

References 85 publications

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“…Based on our data and recently published results, 55 it appears that hypoxemia reduces mitochondrial ROS production, which is essential for progression of cells through G0/G1 phase of mitosis. Higher levels of ROS production are required for cells to progress through S phase and G2/M phase.…”

Section: Discussionsupporting

confidence: 79%

“…Interestingly, there was a downregulation in genes that promote the G1 to S phase transition (Figure 6C). These changes in expression of genes that regulate the G1 to S phase transition of the cell cycle, together with the reduced levels of mitochondrial ROS production 55 may help explain why so few of the hypoxic RV and LV myocytes demonstrated DNA synthesis and cell division (Figures 2C, 3E, 4C, and 4D). Cardiomyocyte hypertrophy in hypoxia mice (Figure 1E) may also be related to an increase in genes involved in DNA synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Since RV myocytes were subjected to hypoxia and RV pressure overload, the small amount of proliferation likely resulted from the effects of pressure overload on the myocytes in this chamber. The low production of ROS in hypoxia 55 could prevent an increase in the activation of G1 to S phase transition genes, but this will require additional study.…”

Section: Discussionmentioning

confidence: 99%

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Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation

Johnson

Yang

Bian

et al. 2023

Circulation Research

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BACKGROUND: A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. METHODS: EdU-containing mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were placed in a hypoxia chamber, and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% oxygen for 2 weeks before terminal studies. Myocyte proliferation was also studied with a mosaic analysis with double markers mouse model. RESULTS: Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced an increase (0.01±0.01% in normoxia to 0.11±0.09% in hypoxia) in the number of EdU+ RV cardiomyocytes, with no effect on LV myocytes in male C57BL/6 mice. Similar results were observed in female mice. Furthermore, in mosaic analysis with double markers mice, hypoxia induced a significant increase in RV myocyte proliferation (0.03±0.03% in normoxia to 0.32±0.15% in hypoxia of RFP+ myocytes), with no significant change in LV myocyte proliferation. RNA sequencing showed upregulation of mitotic cell cycle genes and a downregulation of Cullin genes, which promote the G1 to S phase transition in hypoxic mice. There was significant proliferation of nonmyocytes and mild cardiac fibrosis in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression following hypoxia. CONCLUSIONS: Systemic hypoxia induces a global hypertrophic stress response that was associated with increased RV proliferation, and while LV myocytes did not show increased proliferation, our results minimally confirm previous reports that hypoxia can induce cardiomyocyte cell cycle activity in vivo.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation

Johnson

Yang

Bian

et al. 2023

Circulation Research

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“…Notably, ROS level varied during the cell cycle progression. Cellular ROS increased from G1 to G2/M phases [ 23 , 39 , 40 ]. Ki67 expression level changes along with cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

SRSF3-Mediated Ki67 Exon 7-Inclusion Promotes Head and Neck Squamous Cell Carcinoma Progression via Repressing AKR1C2

Liu

Lin

Huang

et al. 2023

IJMS

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Ki67 is a well-known proliferation marker with a large size of around 350 kDa, but its biological function remains largely unknown. The roles of Ki67 in tumor prognosis are still controversial. Ki67 has two isoforms generated by alternative splicing of exon 7. The roles and regulatory mechanisms of Ki67 isoforms in tumor progression are not clear. In the present study, we surprisingly find that the increased inclusion of Ki67 exon 7, not total Ki67 expression level, was significantly associated with poor prognosis in multiple cancer types, including head and neck squamous cell carcinoma (HNSCC). Importantly, the Ki67 exon 7-included isoform is required for HNSCC cell proliferation, cell cycle progression, cell migration, and tumorigenesis. Unexpectedly, Ki67 exon 7-included isoform is positively associated with intracellular reactive oxygen species (ROS) level. Mechanically, splicing factor SRSF3 could promote exon 7 inclusion via its two exonic splicing enhancers. RNA-seq revealed that aldo-keto reductase AKR1C2 is a novel tumor-suppressive gene targeted by Ki67 exon 7-included isoform in HNSCC cells. Our study illuminates that the inclusion of Ki67 exon 7 has important prognostic value in cancers and is essential for tumorigenesis. Our study also suggested a new SRSF3/Ki67/AKR1C2 regulatory axis during HNSCC tumor progression.

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“…In support of this model, we observed that mTORC1, a multi-molecular complex integrating mitogenic and metabolic pathways to promote anabolism and known to control cell cycle in AML [51,52] could regulate G 0 /G 1 transition dependent on ROS content in AML. Interestingly, recent studies showed that ROS produced by mitochondrial respiration promote CDK2 phosphorylation [53], suggesting that ROS could have critical functions as signaling molecules to regulate cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia

et al. 2023

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Mitochondrial metabolism recently emerged as a critical dependency in acute myeloid leukemia (AML). The shape of mitochondria is tightly regulated by dynamin GTPase proteins, which drive opposing fusion and fission forces to consistently adapt bioenergetics to the cellular context. Here, we showed that targeting mitochondrial fusion was a new vulnerability of AML cells, when assayed in patient-derived xenograft (PDX) models. Genetic depletion of mitofusin 2 (MFN2) or optic atrophy 1 (OPA1) or pharmacological inhibition of OPA1 (MYLS22) blocked mitochondrial fusion and had significant anti-leukemic activity, while having limited impact on normal hematopoietic cells ex vivo and in vivo. Mechanistically, inhibition of mitochondrial fusion disrupted mitochondrial respiration and reactive oxygen species production, leading to cell cycle arrest at the G0/G1 transition. These results nominate the inhibition of mitochondrial fusion as a promising therapeutic approach for AML.

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A ROS-dependent mechanism promotes CDK2 phosphorylation to drive progression through S phase

Cited by 66 publications

References 85 publications

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation

Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation

SRSF3-Mediated Ki67 Exon 7-Inclusion Promotes Head and Neck Squamous Cell Carcinoma Progression via Repressing AKR1C2

Mitochondrial fusion is a therapeutic vulnerability of acute myeloid leukemia

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