scholarly journals Human Keratinocytes That Express hTERT and Also Bypass a p16INK4a-Enforced Mechanism That Limits Life Span Become Immortal yet Retain Normal Growth and Differentiation Characteristics

2000 ◽  
Vol 20 (4) ◽  
pp. 1436-1447 ◽  
Author(s):  
Mark A. Dickson ◽  
William C. Hahn ◽  
Yasushi Ino ◽  
Vincent Ronfard ◽  
Jenny Y. Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Life Span ◽  
Cell Cycle Control ◽  
Growth Control ◽  
Cell Types ◽  
Mesothelial Cells ◽  
Population Doubling ◽  
Htert Expression ◽  
Normal Human

ABSTRACT Normal human cells exhibit a limited replicative life span in culture, eventually arresting growth by a process termed senescence. Progressive telomere shortening appears to trigger senescence in normal human fibroblasts and retinal pigment epithelial cells, as ectopic expression of the telomerase catalytic subunit, hTERT, immortalizes these cell types directly. Telomerase expression alone is insufficient to enable certain other cell types to evade senescence, however. Such cells, including keratinocytes and mammary epithelial cells, appear to require loss of the pRB/p16INK4a cell cycle control mechanism in addition to hTERT expression to achieve immortality. To investigate the relationships among telomerase activity, cell cycle control, senescence, and differentiation, we expressed hTERT in two epithelial cell types, keratinocytes and mesothelial cells, and determined the effect on proliferation potential and on the function of cell-type-specific growth control and differentiation systems. Ectopic hTERT expression immortalized normal mesothelial cells and a premalignant, p16INK4a-negative keratinocyte line. In contrast, when four keratinocyte strains cultured from normal tissue were transduced to express hTERT, they were incompletely rescued from senescence. After reaching the population doubling limit of their parent cell strains, hTERT+ keratinocytes entered a slow growth phase of indefinite length, from which rare, rapidly dividing immortal cells emerged. These immortal cell lines frequently had sustained deletions of the CDK2NA/INK4A locus or otherwise were deficient in p16INK4a expression. They nevertheless typically retained other keratinocyte growth controls and differentiated normally in culture and in xenografts. Thus, keratinocyte replicative potential is limited by a p16INK4a-dependent mechanism, the activation of which can occur independent of telomere length. Abrogation of this mechanism together with telomerase expression immortalizes keratinocytes without affecting other major growth control or differentiation systems.

scholarly journals Systems analysis of the transcriptional response of human ileocecal epithelial cells to Clostridium difficile toxins and effects on cell cycle control

2012 ◽  
Vol 6 (1) ◽  
pp. 2 ◽  
Author(s):  
Kevin M D'Auria ◽  
Gina M Donato ◽  
Mary C Gray ◽  
Glynis L Kolling ◽  
Cirle A Warren ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clostridium Difficile ◽  
Epithelial Cells ◽  
Systems Analysis ◽  
Cell Cycle Control ◽  
Transcriptional Response

Discordant regulatory changes in monocrotaline-induced megalocytosis of lung arterial endothelial and alveolar epithelial cells

2006 ◽  
Vol 290 (6) ◽  
pp. L1216-L1226 ◽  
Author(s):  
Somshuvra Mukhopadhyay ◽  
Pravin B. Sehgal
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Dna Synthesis ◽  
A549 Cells ◽  
Cell Types ◽  
Alveolar Epithelial Cells ◽  
Cell Type ◽  
Alveolar Epithelial ◽  
Unfolded Protein ◽  
Cell Cycle Regulatory Proteins

Monocrotaline (MCT) causes pulmonary hypertension in the rat by a mechanism characterized by megalocytosis (enlarged cells with enlarged endoplasmic reticulum and Golgi and a cell cycle arrest) of pulmonary arterial endothelial (PAEC), arterial smooth muscle, and type II alveolar epithelial cells. In cell culture, although megalocytosis is associated with a block in entry into mitosis in both lung endothelial and epithelial cells, DNA synthesis is stimulated in endothelial but inhibited in epithelial cells. The molecular mechanism(s) for this dichotomy are unclear. While MCTP-treated PAEC and lung epithelial (A549) cells both showed an increase in the “promitogenic” transcription factor STAT3 levels and in the IL-6-induced nuclear pool of PY-STAT3, this was transcriptionally inactive in A549 but not in PAEC cells. This lack of transcriptional activity of STAT3 in A549 cells correlated with the cytoplasmic sequestration of the STAT3 coactivators CBP/p300 and SRC1/NcoA in A549 cells but not in PAEC. Both cell types displayed a Golgi trafficking block, loss of caveolin-1 rafts, and increased nuclear Ire1α, but an incomplete unfolded protein response (UPR) with little change in levels of UPR-induced chaperones including GRP78/BiP. There were discordant alterations in cell cycle regulatory proteins in the two cell types such as increase in levels of both cyclin D1 and p21 simultaneously, but with a decrease in cdc2/cdk1, a kinase required for entry into mitosis. While both cell types showed increased cytoplasmic geminin, the DNA synthesis-initiating protein Cdt1 was predominantly nuclear in PAEC but remained cytoplasmic in A549 cells, consistent with the stimulation of DNA synthesis in the former but an inhibition in the latter cell type. Thus differences in cell type-specific alterations in subcellular trafficking of critical regulatory molecules (such as CBP/p300, SRC1/NcoA, Cdt1) likely account for the dichotomy of the effects of MCTP on DNA synthesis in endothelial and epithelial cells.

scholarly journals Deceleration of cell cycle underpins a switch from proliferative- to terminal division in plant stomatal lineage

2021 ◽  
Author(s):  
Soon-Ki Han ◽  
Jiyuan Yang ◽  
Machiko Arakawa ◽  
Rie Iwasaki ◽  
Tomoaki Sakamoto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
Cell Cycle Control ◽  
Control Plant ◽  
Time Lapse ◽  
Cell Types ◽  
Symmetric Division ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Asymmetric Divisions ◽  
Stomatal Lineage

Differentiation of specialized cell types from self-renewing progenitors requires precise cell cycle control. Plant stomata are generated through asymmetric divisions of a stem-cell-like precursor meristemoid followed by the single symmetric division that creates an adjustable pore surrounded by paired guard cells. The stomatal-lineage-specific transcription factor MUTE terminates the asymmetric divisions and triggers differentiation. However, the role of cell cycle machinery in this transition remains unknown. Through time-lapse imaging, we discover that the symmetric division is slower than the asymmetric division. We identify a plant-specific cyclin-dependent kinase inhibitor, SIAMESE-RELATED4 (SMR4), as a molecular brake that decelerates cell cycle during this transition. SMR4 is directly induced by MUTE and transiently accumulates in differentiating meristemoids. SMR4 physically and functionally associates with CYCD3;1 and extends G1-phase of asymmetric divisions. By contrast, SMR4 fails to interact with CYCD5;1, a MUTE-induced G1 cyclin, and permits the symmetric division. Our work unravels a molecular framework of the proliferation-to-differentiation switch within the stomatal lineage and suggests that a timely proliferative cell cycle is critical for the stomatal fate specification.

scholarly journals ING3 and ING4 immunoexpression and their relation to the development of benign odontogenic lesions

2021 ◽  
Vol 32 (4) ◽  
pp. 74-82
Author(s):  
Yailit del Carmen Martinez-Vargas ◽  
Tiago João da Silva-Filho ◽  
Denise Hélen Imaculada Pereira de Oliveira ◽  
Rani Iani Costa Gonçalo ◽  
Lélia Maria Guedes Queiroz
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Repair ◽  
Tumor Suppressor ◽  
Epithelial Cells ◽  
Gene Family ◽  
Tumor Suppressor Genes ◽  
Cell Cycle Control ◽  
P Value ◽  
Proliferation And Apoptosis

Abstract The Inhibitor of Growth (ING) gene family is a group of tumor suppressor genes that play important roles in cell cycle control, senescence, DNA repair, cell proliferation, and apoptosis. However, inactivation and downregulation of these proteins have been related in some neoplasms. The present study aimed to evaluate the immunohistochemical profiles of ING3 and ING4 proteins in a series of benign epithelial odontogenic lesions. Methods: The sample comprised of 20 odontogenic keratocysts (OKC), 20 ameloblastomas (AM), and 15 adenomatoid odontogenic tumors (AOT) specimens. Nuclear and cytoplasmic immunolabeling of ING3 and ING4 were semi-quantitatively evaluated in epithelial cells of the odontogenic lesions, according to the percentage of immunolabelled cells in each case. Descriptive and statistics analysis were computed, and the p-value was set at 0.05. Results: No statistically significant differences were found in cytoplasmic and nuclear ING3 immunolabeling among the studied lesions. In contrast, AOTs presented higher cytoplasmic and nuclear ING4 labeling compared to AMs (cytoplasmic p-value = 0.01; nuclear p-value < 0.001) and OKCs (nuclear p-value = 0.007). Conclusion: ING3 and ING4 protein downregulation may play an important role in the initiation and progression of more aggressive odontogenic lesions, such as AMs and OKCs.

scholarly journals Cell Cycle Control of a Holdfast Attachment Gene inCaulobacter crescentus

1999 ◽  
Vol 181 (4) ◽  
pp. 1118-1125 ◽  
Author(s):  
Raji S. Janakiraman ◽  
Yves V. Brun
Keyword(s):  
Cell Cycle ◽  
Polar Region ◽  
Caulobacter Crescentus ◽  
Cell Cycle Control ◽  
Indirect Evidence ◽  
Cell Types ◽  
Transmission Electron ◽  
Different Cell Types ◽  
Prosthecate Bacterium ◽  
Maximal Expression

ABSTRACT Attachment to surfaces by the prosthecate bacteriumCaulobacter crescentus is mediated by an adhesive organelle, the holdfast, found at the tip of the stalk. Indirect evidence suggested that the holdfast first appears at the swarmer pole of the predivisional cell. We used fluorescently labeled lectin and transmission electron microscopy to detect the holdfast in different cell types. While the holdfast was readily detectable in stalked cells and at the stalked poles of predivisional cells, we were unable to detect the holdfast in swarmer cells or at the flagellated poles of predivisional cells. This suggests that exposure of the holdfast to the outside of the cell occurs during the differentiation of swarmer to stalked cells. To investigate the timing of holdfast synthesis and exposure to the outside of the cell, we have examined the regulation of a holdfast attachment gene, hfaA. The hfaA gene is part of a cluster of four genes (hfaABDC), identified in strain CB2A and involved in attachment of the holdfast to the polar region of the cell. We have identified the hfaA gene in the synchronizable C. crescentus strain CB15. The sequence of the CB2A hfaA promoter suggested that it was regulated by ς54. We show that the transcription of hfaAfrom either strain is not dependent on ς54. Using ahfaA-lacZ fusion, we show that the transcription ofhfaA is temporally regulated during the cell cycle, with maximal expression in late-predivisional cells. This increase in expression is largely due to the preferential transcription ofhfaA in the swarmer pole of the predivisional cell.

scholarly journals Role of Human Cytomegalovirus Immediate-Early Proteins in Cell Growth Control

2000 ◽  
Vol 74 (17) ◽  
pp. 8028-8037 ◽  
Author(s):  
Jonathan P. Castillo ◽  
Andrew D. Yurochko ◽  
Timothy F. Kowalik
Keyword(s):  
Cell Cycle ◽  
Human Cytomegalovirus ◽  
P53 Protein ◽  
Cell Cycle Control ◽  
Growth Control ◽  
S Phase ◽  
Immediate Early ◽  
Cell Cycle Distribution ◽  
Cell Cycle Exit ◽  
Delay Cell

ABSTRACT Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus that has been implicated in several disorders, including an association between HCMV reactivation and the overproliferation of arterial smooth muscle cells observed in restenosis. Although HCMV can mediate a growth-arrest phenotype in infected cells, the virus can also promote an environment conducive to proliferation. Here, we present evidence that the HCMV immediate-early (IE) proteins, IE1-72 and IE2-86, may be responsible for inducing this proliferative environment by altering cell cycle control. We find that expression of either of these IE proteins can alter the cell cycle distribution of randomly cycling cells towards S and G2/M phases. Additionally, we find that expression of IE2-86, but not IE1-72, induces quiescent cells into S phase and delays cell cycle exit. In the absence of p53, IE1-72 expression can induce S phase and delay cell cycle exit. We also demonstrate that p53 protein levels increase in fibroblasts following the expression of IE1-72. The observed accumulation of p53 protein in IE1-72-expressing cells may account for the inability of IE1-72 to induce S phase and delay cell cycle exit. Our data suggest that expression of HCMV IE1-72 and IE2-86 is sufficient to alter the cell cycle to generate an environment conducive to proliferation.

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