scholarly journals The Tumor Suppressor Merlin Is Required for Cell Cycle Exit, Terminal Differentiation, and Cell Polarity in the Developing Murine Lens

2010 ◽  
Vol 51 (7) ◽  
pp. 3611 ◽  
Author(s):  
Luke A. Wiley ◽  
Lisa K. Dattilo ◽  
Kai B. Kang ◽  
Marco Giovannini ◽  
David C. Beebe
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Cell Polarity ◽  
Terminal Differentiation ◽  
Cell Cycle Exit

scholarly journals Chromatin organization changes during the establishment and maintenance of the postmitotic state

2017 ◽  
Author(s):  
Yiqin Ma ◽  
Laura Buttitta
Keyword(s):  
Cell Cycle ◽  
Gene Silencing ◽  
Ectopic Expression ◽  
Terminal Differentiation ◽  
Chromatin Organization ◽  
Cell Cycle Exit ◽  
Heterochromatin Protein 1 ◽  
Developmental Potential ◽  
Close Relationship ◽  
The Face

SummaryBackgroundGenome organization changes during development as cells differentiate. Chromatin motion becomes increasingly constrained and heterochromatin clusters as cells become restricted in their developmental potential. These changes coincide with slowing of the cell cycle, which can also influence chromatin organization and dynamics. Terminal differentiation is often coupled with permanent exit from the cell cycle and existing data suggests a close relationship between a repressive chromatin structure and silencing of the cell cycle in postmitotic cells. Here we examine the relationship between chromatin organization, terminal differentiation and cell cycle exit.ResultsWe focused our studies on the Drosophila wing, where epithelial cells transition from active proliferation to a postmitotic state in a temporally controlled manner. We find there are two stages of G0 in this tissue, a flexible G0 period where cells can be induced to re-enter the cell cycle under specific genetic manipulations and a state we call “robust”, where cells become strongly refractory to cell cycle re-entry. Compromising the flexible G0 by driving ectopic expression of cell cycle activators causes a global disruption of the clustering of heterochromatin-associated histone modifications such as H3K27 trimethylation and H3K9 trimethylation, as well as their associated repressors, Polycomb and heterochromatin protein 1(HP1). However, this disruption is reversible. When cells enter a robust G0 state, even in the presence of ectopic cell cycle activity, clustering of heterochromatin associated modifications are restored. If cell cycle exit is bypassed, cells in the wing continue to terminally differentiate, but heterochromatin clustering is severely disrupted. Heterochromatin-dependent gene silencing does not appear to be required for cell cycle exit, as compromising the H3K27 methyltransferase Enhancer of zeste, and/or HP1 cannot prevent the robust cell cycle exit, even in the face of normally oncogenic cell cycle activities.ConclusionsHeterochromatin clustering during terminal differentiation is a consequence of cell cycle exit, rather than differentiation. Compromising heterochromatin-dependent gene silencing does not disrupt cell cycle exit.

Translational significance of a newly identified hepatocellular carcinoma tumor suppressor gene on chromosome 8p.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15097-e15097
Author(s):  
Han Chong Toh ◽  
Francis Enane ◽  
Marissa Teo ◽  
Hideki Makishima ◽  
JoAnna Ng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Biological Significance ◽  
Suppressor Gene ◽  
Cell Cycle Exit ◽  
Malignant Liver

e15097 Background: After deletion of 17p that removes the tumor suppressor gene (TSG) TP53, deletion of 8p is the next most common chromosome abnormality in hepatocellular carcinoma (HCC). However, 8p TSG are insufficiently defined. Methods: Integrated genomic analysis of HCC and non-malignant liver obtained at therapeutic segmentectomy from the same patients. Results: A minimally deleted region on 8p was identified by SNP array. This incorporated GATA4. Therefore, GATA4 was Sanger sequenced in paired HCC/non-malignant liver: recurrent somatic non-synonymous missense mutations were identified in exon 4 (V267M n=5) or exon 6 (S357T n=6, R362N n=2, T366R n=2). Biallelic abnormalities were deletion and mutation (n=6) or mutation and uniparental disomy (n=4), with mutation or deletion of at least one GATA4 allele in 29/47 (62%) of HCC cases. The other GATA4 exons were mutation free. Although missense mutation is not intrinsically expected to decrease GATA4 expression, GATA4 mRNA was significantly decreased in cases with mutation as well as deletion (p<0.01) compared to non-malignant liver or wild-type GATA4 HCC. GATA4 drives liver differentiation, and the biological significance of GATA4 deficiency was demonstrated by significant enrichment (49%) for liver differentiation genes (p<1.2exp-124, Benjamini corrected) amongst genes with decreased expression in HCC compared to non-malignant liver. From an oncogenesis perspective, the most important of these hepatocyte genes (e.g., HNF4A, CEBPD) antagonize MYC to terminate proliferation: GATA4 introduction (expression vector) into HCC cells containing mutated or deleted GATA4 (HepG2 and PLC respectively) restored HNF4A and CEBPD expression, suppressed MYC protein, upregulated p27/CDKN1B that mediates cell cycle exit by maturation and significantly decreased HCC proliferation without apoptosis. In objectively quantified immunohistochemical analyses (ImageIQ), HCC cases with GATA4 mutation/deletion had significantly increased MYC protein (p<0.05). Conclusions: 8p deletion/GATA4 mutation in HCC suppresses cell cycle exit by maturation, thus complementing 17p deletion that suppresses cell cycle exit by apoptosis.

scholarly journals A Double-Assurance Mechanism Controls Cell Cycle Exit upon Terminal Differentiation in Drosophila

2007 ◽  
Vol 12 (4) ◽  
pp. 631-643 ◽  
Author(s):  
Laura A. Buttitta ◽  
Alexia J. Katzaroff ◽  
Carissa L. Perez ◽  
Aida de la Cruz ◽  
Bruce A. Edgar
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Cell Cycle Exit

scholarly journals Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma

2004 ◽  
Vol 167 (5) ◽  
pp. 925-934 ◽  
Author(s):  
David M. Thomas ◽  
Sandra A. Johnson ◽  
Natalie A. Sims ◽  
Melanie K. Trivett ◽  
John L. Slavin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Osteoblast Differentiation ◽  
Ectopic Expression ◽  
Osteosarcoma Cell ◽  
Cell Cycle Exit ◽  
Retinoblastoma Tumor Suppressor ◽  
Cycle Arrest ◽  
Permanent Cell ◽  
Retinoblastoma Tumor

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma.

scholarly journals The SWI/SNF Subunit/Tumor Suppressor BAF47/INI1 Is Essential in Cell Cycle Arrest upon Skeletal Muscle Terminal Differentiation

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e108858 ◽  
Author(s):  
Véronique Joliot ◽  
Ouardia Ait-Mohamed ◽  
Valentine Battisti ◽  
Julien Pontis ◽  
Ophélie Philipot ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Skeletal Muscle ◽  
Tumor Suppressor ◽  
Cell Cycle Arrest ◽  
Terminal Differentiation ◽  
Cycle Arrest

scholarly journals Tropomodulin3-null mice are embryonic lethal with anemia due to impaired erythroid terminal differentiation in the fetal liver

Blood ◽  
2014 ◽  
Vol 123 (5) ◽  
pp. 758-767 ◽  
Author(s):  
Zhenhua Sui ◽  
Roberta B. Nowak ◽  
Andrea Bacconi ◽  
Nancy E. Kim ◽  
Hui Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Fetal Liver ◽  
Terminal Differentiation ◽  
Cell Types ◽  
Cell Cycle Exit ◽  
Erythroid Progenitors ◽  
Island Formation ◽  
Erythroid Terminal Differentiation ◽  
Embryonic Lethal ◽  
Key Points

Key Points Tmod3 deletion leads to reduced erythroid progenitors and impaired erythroblast survival, cell-cycle exit, and enucleation. Erythroblast-macrophage islands are reduced in the absence of Tmod3, which is required in both cell types for island formation.

scholarly journals The coordination of terminal differentiation and cell cycle exit is mediated through the regulation of chromatin accessibility

2018 ◽  
Author(s):  
Yiqin Ma ◽  
Daniel J McKay ◽  
Laura Buttitta
Keyword(s):  
Cell Cycle ◽  
Terminal Differentiation ◽  
Chromatin Accessibility ◽  
Cell Cycle Gene ◽  
Cell Cycle Regulators ◽  
Cell Cycle Exit ◽  
Cell Cycle Genes ◽  
Repressor Complex ◽  
Pupal Wing ◽  
A Cell

During terminal differentiation most cells will exit the cell cycle and enter into a prolonged or permanent G0. Cell cycle exit is usually initiated through the repression of cell cycle gene expression by formation of a transcriptional repressor complex called DREAM. However when DREAM repressive function is compromised during terminal differentiation, additional unknown mechanisms act to stably repress cycling and ensure robust cell cycle exit. Here we provide evidence that developmentally programmed, temporal changes in chromatin accessibility at a subset of critical cell cycle genes acts to enforce cell cycle exit during terminal differentiation in the Drosophila melanogaster wing. We show that during terminal differentiation, chromatin closes at a set of pupal wing enhancers for the key rate-limiting cell cycle regulators cycE, e2f1 and stg. This closing coincides with wing cells entering a robust postmitotic state that is strongly refractory to cell cycle re-activation. When cell cycle exit is genetically disrupted, chromatin accessibility at cell cycle genes remains largely unaffected and the closing of enhancers at cycE, e2f1 and stg proceeds independent of the cell cycling status. Instead, disruption of cell cycle exit leads to changes in accessibility and expression of a subset of hormone-induced transcription factors involved in the progression of terminal differentiation. Our results uncover a mechanism that acts as a cell cycle-independent timer to limit aberrant cycling in terminally differentiating tissues. In addition, we provide a new molecular description of the cross-talk between cell cycle exit and terminal differentiation during metamorphosis.

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