scholarly journals The Effects of Human BDH2 on the Cell Cycle, Differentiation, and Apoptosis and Associations with Leukemia Transformation in Myelodysplastic Syndrome

2020 ◽  
Vol 21 (9) ◽  
pp. 3033
Author(s):  
Wen-Chi Yang ◽  
Sheng-Fung Lin ◽  
Shu-Chen Wang ◽  
Wan-Chi Tsai ◽  
Chun-Chieh Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Myelodysplastic Syndrome ◽  
De Novo ◽  
Ferritin Level ◽  
Limiting Factor ◽  
Poor Prognostic Factor ◽  
Cycle Arrest ◽  
Differentiation And Proliferation ◽  
Rate Limiting

Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.

scholarly journals p53 protects against genome instability following centriole duplication failure

2015 ◽  
Vol 210 (1) ◽  
pp. 63-77 ◽  
Author(s):  
Bramwell G. Lambrus ◽  
Yumi Uetake ◽  
Kevin M. Clutario ◽  
Vikas Daggubati ◽  
Michael Snyder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Gene Targeting ◽  
Chromosome Segregation ◽  
De Novo ◽  
Genome Instability ◽  
Centriole Duplication ◽  
Cycle Arrest ◽  
Surveillance Mechanism

Centriole function has been difficult to study because of a lack of specific tools that allow persistent and reversible centriole depletion. Here we combined gene targeting with an auxin-inducible degradation system to achieve rapid, titratable, and reversible control of Polo-like kinase 4 (Plk4), a master regulator of centriole biogenesis. Depletion of Plk4 led to a failure of centriole duplication that produced an irreversible cell cycle arrest within a few divisions. This arrest was not a result of a prolonged mitosis, chromosome segregation errors, or cytokinesis failure. Depleting p53 allowed cells that fail centriole duplication to proliferate indefinitely. Washout of auxin and restoration of endogenous Plk4 levels in cells that lack centrioles led to the penetrant formation of de novo centrioles that gained the ability to organize microtubules and duplicate. In summary, we uncover a p53-dependent surveillance mechanism that protects against genome instability by preventing cell growth after centriole duplication failure.

The Bub2-dependent mitotic pathway in yeast acts every cell cycle and regulates cytokinesis

2001 ◽  
Vol 114 (12) ◽  
pp. 2345-2354 ◽  
Author(s):  
Sarah E. Lee ◽  
Sanne Jensen ◽  
Lisa M. Frenz ◽  
Anthony L. Johnson ◽  
Didier Fesquet ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Normal Function ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Checkpoint Activation ◽  
Cycle Arrest ◽  
A Cell ◽  
Entire Cell ◽  
Cycle Dependent ◽  
Rate Limiting

In eukaryotes an abnormal spindle activates a conserved checkpoint consisting of the MAD and BUB genes that results in mitotic arrest at metaphase. Recently, we and others identified a novel Bub2-dependent branch to this checkpoint that blocks mitotic exit. This cell-cycle arrest depends upon inhibition of the G-protein Tem1 that appears to be regulated by Bfa1/Bub2, a two-component GTPase-activating protein, and the exchange factor Lte1. Here, we find that Bub2 and Bfa1 physically associate across the entire cell cycle and bind to Tem1 during mitosis and early G1. Bfa1 is multiply phosphorylated in a cell-cycle-dependent manner with the major phosphorylation occurring in mitosis. This Bfa1 phosphorylation is Bub2-dependent. Cdc5, but not Cdc15 or Dbf2, partly controls the phosphorylation of Bfa1 and also Lte1. Following spindle checkpoint activation, the cell cycle phosphorylation of Bfa1 and Lte1 is protracted and some species are accentuated. Thus, the Bub2-dependent pathway is active every cell cycle and the effect of spindle damage is simply to protract its normal function. Indeed, function of the Bub2 pathway is also prolonged during metaphase arrests imposed by means other than checkpoint activation. In metaphase cells Bub2 is crucial to restrain downstream events such as actin ring formation, emphasising the importance of the Bub2 pathway in the regulation of cytokinesis. Our data is consistent with Bub2/Bfa1 being a rate-limiting negative regulator of downstream events during metaphase.

scholarly journals Targeting the p27 E3 ligase SCFSkp2 results in p27- and Skp2-mediated cell-cycle arrest and activation of autophagy

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4690-4699 ◽  
Author(s):  
Qing Chen ◽  
Weilin Xie ◽  
Deborah J. Kuhn ◽  
Peter M. Voorhees ◽  
Antonia Lopez-Girona ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
High Throughput Screening ◽  
Antitumor Agents ◽  
Plasma Cells ◽  
E3 Ligase ◽  
Poor Prognostic Factor ◽  
Cycle Arrest ◽  
Ligase Function

Abstract Decreased p27Kip1 levels are a poor prognostic factor in many malignancies, and can occur through up-regulation of SCFSkp2 E3 ligase function, resulting in enhanced p27 ubiquitination and proteasome-mediated degradation. While proteasome inhibitors stabilize p27Kip1, agents inhibiting SCFSkp2 may represent more directly targeted drugs with the promise of enhanced efficacy and reduced toxicity. Using high-throughput screening, we identified Compound A (CpdA), which interfered with SCFSkp2 ligase function in vitro, and induced specific accumulation of p21 and other SCFSkp2 substrates in cells without activating a heat-shock protein response. CpdA prevented incorporation of Skp2 into the SCFSkp2 ligase, and induced G1/S cell-cycle arrest as well as SCFSkp2- and p27-dependent cell killing. This programmed cell death was caspase-independent, and instead occurred through activation of autophagy. In models of multiple myeloma, CpdA overcame resistance to dexamethasone, doxorubicin, and melphalan, as well as to bortezomib, and also acted synergistically with this proteasome inhibitor. Importantly, CpdA was active against patient-derived plasma cells and both myeloid and lymphoblastoid leukemia blasts, and showed preferential activity against neoplastic cells while relatively sparing other marrow components. These findings provide a rational framework for further development of SCFSkp2 inhibitors as a novel class of antitumor agents.

Intestinal aspects of lipid absorption: in review

1989 ◽  
Vol 67 (3) ◽  
pp. 179-191 ◽  
Author(s):  
A. B. R. Thomson ◽  
M. Keelan ◽  
M. L. Garg ◽  
M. T. Clandinin
Keyword(s):  
Dietary Fat ◽  
De Novo ◽  
Membrane Lipid ◽  
Dietary Fats ◽  
Lipid Absorption ◽  
Limiting Factor ◽  
Adaptive Responses ◽  
Phospholipid Biosynthesis ◽  
New Knowledge ◽  
Rate Limiting

The rapidly evolving field of lipid absorption is reviewed with the thrust of new knowledge focused on the interpendency of the luminal and cellular phases of absorption. To date little attention has been paid to factors that regulate the phospholipid biosynthesis in the enterocyte. The availability of 20:4ω6 may be the rate-limiting factor for phospholipid synthesis. The source of 20:4ω6 is unknown, whether it be synthesized de novo the enterocyte or entirely originating from degradation of bile phospholipid. It has been established that dietary fat can modulate the enterocyte membrane lipid composition and transport properties. Specified fats such as as fish oils rich in 20:5ω3 and 22:6ω3 have been implicated as protective against hypercholesterolemia. However, the effects of these dietary fats on the transport of nutrients across the enterocyte are not yet known, nor are the mechanisms responsible for the adaptive responses of the brush border identified.

scholarly journals Histone supply regulates S phase timing and cell cycle progression

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Ufuk Günesdogan ◽  
Herbert Jäckle ◽  
Alf Herzig
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
De Novo ◽  
S Phase ◽  
Histone Genes ◽  
Nucleosome Assembly ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
A Cell ◽  
Surveillance Mechanism

Eukaryotes package DNA into nucleosomes that contain a core of histone proteins. During DNA replication, nucleosomes are disrupted and re-assembled with newly synthesized histones and DNA. Despite much progress, it is still unclear why higher eukaryotes contain multiple core histone genes, how chromatin assembly is controlled, and how these processes are coordinated with cell cycle progression. We used a histone null mutation of Drosophila melanogaster to show that histone supply levels, provided by a defined number of transgenic histone genes, regulate the length of S phase during the cell cycle. Lack of de novo histone supply not only extends S phase, but also causes a cell cycle arrest during G2 phase, and thus prevents cells from entering mitosis. Our results suggest a novel cell cycle surveillance mechanism that monitors nucleosome assembly without involving the DNA repair pathways and exerts its effect via suppression of CDC25 phosphatase String expression.

Cell cycle arrest allows centrin translation but not basal body formation during spermiogenesis inMarsilea

2001 ◽  
Vol 114 (23) ◽  
pp. 4265-4272 ◽  
Author(s):  
Chiawei W. Tsai ◽  
Stephen M. Wolniak
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
De Novo ◽  
Cyclin B ◽  
Basal Bodies ◽  
Cycle Arrest ◽  
Essentially Normal ◽  
Marsilea Vestita ◽  
Stored Mrna ◽  
Cytoplasmic Particle

Spermiogenesis in the water fern Marsilea vestita is a rapid process that requires the de novo formation of basal bodies in a cytoplasmic particle known as a blepharoplast. Spermiogenesis is activated by placing dry spores into water and is dependent upon the translation of new proteins from stored mRNAs with little, if any, new transcription. We looked at the necessity of cell division cycles in the gametophyte as a prerequisite for the activation of centrin translation and for the consequent formation of blepharoplasts. Cell cycle arrest was induced by treatments of gametophytes with hydroxyurea, with olomoucine, or after RNAi, employing dsRNA derived from Marsilea cyclin A or cyclin B. In all cases, centrin is translated from stored mRNA at the normal time, approximately 4 hours after imbibition, and it accumulates to maximal levels ∼6 hours after imbibition. In spite of the fact that centrin is translated at essentially normal times and accumulates to nearly normal levels, no blepharoplasts form in the gametophytes where division cycles have been disrupted. These results provide a clear demonstration that the new translation of centrin, by itself, is insufficient for blepharoplast formation, the de novo formation of basal bodies, and the assembly of a motile apparatus.

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