Cell cycle-dependent degradation of the methyltransferase SETD3 attenuates cell proliferation and liver tumorigenesis

Embryogenesis requires an exquisite regulation of cell proliferation, cell cycle withdrawal and differentiation into a massively diverse range of cells at the correct time and place. Stem cells also remain to varying extents in different adult tissues, acting in tissue homeostasis and repair. Therefore, regulated proliferation and subsequent differentiation of stem and progenitor cells remains pivotal throughout life. Recent advances have characterised the cell cycle dynamics, epigenetics, transcriptome and proteome accompanying the transition from proliferation to differentiation, revealing multiple bidirectional interactions between the cell cycle machinery and factors driving differentiation. Here, we focus on a direct mechanistic link involving phosphorylation of differentiation-associated transcription factors by cell cycle-associated Cyclin-dependent kinases. We discuss examples from the three embryonic germ layers to illustrate this regulatory mechanism that co-ordinates the balance between cell proliferation and differentiation.

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Pendulin, a Drosophila protein with cell cycle-dependent nuclear localization, is required for normal cell proliferation.

The Journal of Cell Biology ◽

10.1083/jcb.129.6.1491 ◽

1995 ◽

Vol 129 (6) ◽

pp. 1491-1507 ◽

Cited By ~ 79

Author(s):

P Küssel ◽

M Frasch

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Nuclear Localization ◽

Growth Regulation ◽

Tandem Repeats ◽

Sequence Similarity ◽

Intracellular Localization ◽

Abnormal Development ◽

Embryonic Cells ◽

Cycle Dependent

We describe the dynamic intracellular localization of Drosophila Pendulin and its role in the control of cell proliferation. Pendulin is a new member of a superfamily of proteins which contains Armadillo (Arm) repeats and displays extensive sequence similarities with the Srp1 protein from yeast, with RAG-1 interacting proteins from humans, and with the importin protein from Xenopus. Almost the entire polypeptide chain of Pendulin is composed of degenerate tandem repeats of approximately 42 amino acids each. A short NH2-terminal domain contains adjacent consensus sequences for nuclear localization and cdc2 kinase phosphorylation. The subcellular distribution of Pendulin is dependent on the phase of cell cycle. During interphase, Pendulin protein is exclusively found in the cytoplasm of embryonic cells. At the transition between G2 and M-phase, Pendulin rapidly translocates into the nuclei where it is distributed throughout the nucleoplasm and the areas around the chromosomes. In the larval CNS, Pendulin is predominantly expressed in the dividing neuroblasts, where it undergoes the same cell cycle-dependent redistribution as in embryos. Pendulin is encoded by the oho31 locus and is expressed both maternally and zygotically. We describe the phenotypes of recessive lethal mutations in the oho31 gene that result in a massive decrease or loss of zygotic Pendulin expression. Hematopoietic cells of mutant larvae overproliferate and form melanotic tumors, suggesting that Pendulin normally acts as a blood cell tumor suppressor. In contrast, growth and proliferation in imaginal tissues are reduced and irregular, resulting in abnormal development of imaginal discs and the CNS of the larvae. This phenotype shows that Pendulin is required for normal growth regulation. Based on the structure of the protein, we propose that Pendulin may serve as an adaptor molecule to form complexes with other proteins. The sequence similarity with importin indicates that Pendulin may play a role in the nuclear import of karyophilic proteins and some of these may be required for the normal transmission and function of proliferative signals in the cells.

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Studies on the kinetics of expression of cell cycle dependent proto-oncogenes during mitogen-induced liver cell proliferation

Cancer Letters ◽

10.1016/0304-3835(89)90186-9 ◽

1989 ◽

Vol 47 (1-2) ◽

pp. 115-119 ◽

Cited By ~ 13

Author(s):

P. Coni ◽

F.A. Bignone ◽

G. Pichiri ◽

G.M. Ledda-Columbano ◽

A. Columbano ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Liver Cell ◽

Cycle Dependent ◽

Kinetics Of

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Investigation on Cell Proliferation with a New Antibody against Thymidine Kinase 1

Analytical Cellular Pathology ◽

10.1155/2001/658312 ◽

2001 ◽

Vol 23 (1) ◽

pp. 11-19 ◽

Cited By ~ 26

Author(s):

Naining Wang ◽

Qimin He ◽

Sven Skog ◽

Staffan Eriksson ◽

Bernhard Tribukait

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Thymidine Kinase ◽

Specific Marker ◽

Thymidine Kinase 1 ◽

C Terminus ◽

Proliferation Activity ◽

Cycle Dependent ◽

Cellular Dna ◽

Archival Specimens

The cytosolic thymidine kinase 1 (TK1) is one of the enzymes involved in DNA replication. Based on biochemical studies, TK1 is activated at late G1 of cell cycle, and its activity correlates with the cell proliferation. We have developed a polyclonal anti‐TK1 antibody against a synthetic peptide from the C‐terminus of human TK1. Using this antibody, here we demonstrate the exclusive location of TK1 in the cytoplasm of cells. Cell cycle dependent TK1 expression was studied by simultaneous fluorescence staining for TK1 and bromodeoxyuridine, by using elutriated cells, and by quantitation of the amount TK1 in relation to the cellular DNA content. TK1, which was strongly expressed in the cells in S+G2 period, raised at late G1 and decreased during mitosis. The amount of TK1 increased three folds from late G1 to G2. TK1 positive cells were demonstrated in areas of proliferation activity of various normal and malignant tissues. The new anti‐TK1 antibody works in archival specimens and is a specific marker of cell proliferation.

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Rat Aortic Smooth-Muscle Cell Proliferation Is Bidirectionally Regulated in a Cell Cycle-Dependent Manner via PACAP/VIP Type 2 Receptora

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1998.tb11165.x ◽

1998 ◽

Vol 865 (1 VIP, PACAP, A) ◽

pp. 73-81 ◽

Cited By ~ 19

Author(s):

ATSURO MIYATA ◽

KUMI SATO ◽

JUN HINO ◽

HIROKI TAMAKAWA ◽

HISAYUKI MATSUO ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Smooth Muscle ◽

Smooth Muscle Cell ◽

Dependent Manner ◽

Aortic Smooth Muscle Cell ◽

Aortic Smooth Muscle ◽

A Cell ◽

Cycle Dependent

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Trifluoperazine Inhibits Mesangial Cell Proliferation by Arresting Cell Cycle-Dependent Mechanisms

Medical Science Monitor ◽

10.12659/msm.902522 ◽

2017 ◽

Vol 23 ◽

pp. 3461-3469 ◽

Cited By ~ 2

Author(s):

Baodong Wang ◽

Xiaoshuang Zhou ◽

Yanqin Wang ◽

Rongshan Li

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Mesangial Cell ◽

Mesangial Cell Proliferation ◽

Cycle Dependent

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Autoimmunity to the cell cycle-dependent centromere protein p330d/CENP-F in disorders associated with cell proliferation

Journal of Autoimmunity ◽

10.1016/0896-8411(95)90009-8 ◽

1995 ◽

Vol 8 (4) ◽

pp. 575-586 ◽

Cited By ~ 45

Author(s):

Carlos A. Casiano ◽

Rene L. Humbel ◽

Carol Peebles ◽

Giovanni Covini ◽

Eng M. Tan

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Centromere Protein ◽

Cycle Dependent

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PTOV1 Enables the Nuclear Translocation and Mitogenic Activity of Flotillin-1, a Major Protein of Lipid Rafts

Molecular and Cellular Biology ◽

10.1128/mcb.25.5.1900-1911.2005 ◽

2005 ◽

Vol 25 (5) ◽

pp. 1900-1911 ◽

Cited By ~ 66

Author(s):

Anna Santamaría ◽

Elisabeth Castellanos ◽

Valentí Gómez ◽

Patricia Benedit ◽

Jaime Renau-Piqueras ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Nuclear Localization ◽

Nuclear Translocation ◽

Subcellular Fractionation ◽

Major Protein ◽

Dependent Manner ◽

Protein Levels ◽

A Cell ◽

Cycle Dependent

ABSTRACT PTOV1 is a mitogenic protein that shuttles between the nucleus and the cytoplasm in a cell cycle-dependent manner. It consists of two homologous domains arranged in tandem that constitute a new class of protein modules. We show here that PTOV1 interacts with the lipid raft protein flotillin-1, with which it copurifies in detergent-insoluble floating fractions. Flotillin-1 colocalized with PTOV1 not only at the plasma membrane but, unexpectedly, also in the nucleus, as demonstrated by immunocytochemistry and subcellular fractionation of endogenous and exogenous flotillin-1. Flotillin-1 entered the nucleus concomitant with PTOV1, shortly before the initiation of the S phase. Protein levels of PTOV1 and flotillin-1 oscillated during the cell cycle, with a peak in S. Depletion of PTOV1 significantly inhibited nuclear localization of flotillin-1, whereas depletion of flotillin-1 did not affect nuclear localization of PTOV1. Depletion of either protein markedly inhibited cell proliferation under basal conditions. Overexpression of PTOV1 or flotillin-1 strongly induced proliferation, which required their localization to the nucleus, and was dependent on the reciprocal protein. These observations suggest that PTOV1 assists flotillin-1 in its translocation to the nucleus and that both proteins are required for cell proliferation.

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Cell cycle-dependent expression of potassium channels and cell proliferation in rat mesenchymal stem cells from bone marrow

Cell Proliferation ◽

10.1111/j.1365-2184.2007.00458.x ◽

2007 ◽

Vol 40 (5) ◽

pp. 656-670 ◽

Cited By ~ 55

Author(s):

X. L. Deng ◽

C. P. Lau ◽

K. Lai ◽

K. F. Cheung ◽

G. K. Lau ◽

...

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Bone Marrow ◽

Cell Proliferation ◽

Mesenchymal Stem Cells ◽

Potassium Channels ◽

Cycle Dependent

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Acetylation of Mammalian ADA3 Is Required for Its Functional Roles in Histone Acetylation and Cell Proliferation

Molecular and Cellular Biology ◽

10.1128/mcb.00342-16 ◽

2016 ◽

Vol 36 (19) ◽

pp. 2487-2502 ◽

Cited By ~ 4

Author(s):

Shakur Mohibi ◽

Shashank Srivastava ◽

Aditya Bele ◽

Sameer Mirza ◽

Hamid Band ◽

...

Keyword(s):

Cell Cycle ◽

Cell Proliferation ◽

Histone Acetylation ◽

Cell Cycle Progression ◽

Site Directed Mutagenesis ◽

Dependent Manner ◽

Cycle Progression ◽

Functional Roles ◽

A Cell ◽

Cycle Dependent

Alteration/deficiency in activation 3 (ADA3) is an essential component of specific histone acetyltransferase (HAT) complexes. We have previously shown that ADA3 is required for establishing global histone acetylation patterns and for normal cell cycle progression (S. Mohibi et al., J Biol Chem 287:29442–29456, 2012,http://dx.doi.org/10.1074/jbc.M112.378901). Here, we report that these functional roles of ADA3 require its acetylation. We show that ADA3 acetylation, which is dynamically regulated in a cell cycle-dependent manner, reflects a balance of coordinated actions of its associated HATs, GCN5, PCAF, and p300, and a new partner that we define, the deacetylase SIRT1. We use mass spectrometry and site-directed mutagenesis to identify major sites of ADA3 acetylated by GCN5 and p300. Acetylation-defective mutants are capable of interacting with HATs and other components of HAT complexes but are deficient in their ability to restore ADA3-dependent global or locus-specific histone acetylation marks and cell proliferation inAda3-deleted murine embryonic fibroblasts (MEFs). Given the key importance of ADA3-containing HAT complexes in the regulation of various biological processes, including the cell cycle, our study presents a novel mechanism to regulate the function of these complexes through dynamic ADA3 acetylation.

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