scholarly journals Hypoxia-Inducible Factor 1α Is Essential for Cell Cycle Arrest during Hypoxia

2003 ◽  
Vol 23 (1) ◽  
pp. 359-369 ◽  
Author(s):  
Nobuhito Goda ◽  
Heather E. Ryan ◽  
Bahram Khadivi ◽  
Wayne McNulty ◽  
Robert C. Rickert ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Hypoxia Inducible Factor ◽  
Growth Arrest ◽  
Cell Types ◽  
Low Oxygen ◽  
Double Knockout ◽  
Cycle Arrest

ABSTRACT A classical cellular response to hypoxia is a cessation of growth. Hypoxia-induced growth arrest differs in different cell types but is likely an essential aspect of the response to wounding and injury. An important component of the hypoxic response is the activation of the hypoxia-inducible factor 1 (HIF-1) transcription factor. Although this transcription factor is essential for adaptation to low oxygen levels, the mechanisms through which it influences cell cycle arrest, including the degree to which it cooperates with the tumor suppressor protein p53, remain poorly understood. To determine broadly relevant aspects of HIF-1 function in primary cell growth arrest, we examined two different primary differentiated cell types which contained a deletable allele of the oxygen-sensitive component of HIF-1, the HIF-1α gene product. The two cell types were murine embryonic fibroblasts and splenic B lymphocytes; to determine how the function of HIF-1α influenced p53, we also created double-knockout (HIF-1α null, p53 null) strains and cells. In both cell types, loss of HIF-1α abolished hypoxia-induced growth arrest and did this in a p53-independent fashion. Surprisingly, in all cases, cells lacking both p53 and HIF-1α genes have completely lost the ability to alter the cell cycle in response to hypoxia. In addition, we have found that the loss of HIF-1α causes an increased progression into S phase during hypoxia, rather than a growth arrest. We show that hypoxia causes a HIF-1α-dependent increase in the expression of the cyclin-dependent kinase inhibitors p21 and p27; we also find that hypophosphorylation of retinoblastoma protein in hypoxia is HIF-1α dependent. These data demonstrate that the transcription factor HIF-1 is a major regulator of cell cycle arrest in primary cells during hypoxia.

scholarly journals Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function.

1996 ◽  
Vol 16 (9) ◽  
pp. 4952-4960 ◽  
Author(s):  
R L Ludwig ◽  
S Bates ◽  
K H Vousden
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Sequences ◽  
Transcriptional Activation ◽  
Cellular Response ◽  
Kinase Inhibitor ◽  
Cell Types ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cycle Arrest ◽  
P53 Tumor Suppressor Protein

The p53 tumor suppressor protein is a sequence-specific transcriptional activator, a function which contributes to cell cycle arrest and apoptosis induced by p53 in appropriate cell types. Analysis of a series of p53 point mutants has revealed the potential for selective loss of the ability to transactivate some, but not all, cellular p53-responsive promoters. p53 175P and p53 181L are tumor-derived p53 point mutants which were previously characterized as transcriptionally active. Both mutants retained the ability to activate expression of the cyclin-dependent kinase inhibitor p2lcip1/waf1, and this activity correlated with the ability to induce a G1 cell cycle arrest. However, an extension of this survey to include other p53 targets showed that p53 175P was defective in the activation of p53-responsive sequences derived from the bax promoter and the insulin-like growth factor-binding protein 3 gene (IGF-BP3) promoter, while p53 181L showed loss of the ability to activate a promoter containing IGF-BP3 box B sequences. Failure to activate transcription was also reflected in the reduced ability of the mutants to bind the p53-responsive DNA sequences present in these promoters. These specific defects in transcriptional activation correlated with the impaired apoptotic function displayed by these mutants, and the results suggest that activation of cell cycle arrest genes by p53 can be separated from activation of genes with a role in mediating the p53 apoptotic response. The cellular response to p53 activation may therefore depend, at least in part, on which group of p53-responsive genes become transcriptionally activated.

KRÜPPEL-LIKE TRANSCRIPTION FACTOR 6 (KLF6) OVEREXPRESSION INDUCES CELL CYCLE ARREST AND FUSION OF BEWO CELLS

Placenta ◽  
2019 ◽  
Vol 83 ◽  
pp. e65
Author(s):  
Andrea Lis Miranda ◽  
Lucille Kourdova ◽  
Ana Cristina Racca ◽  
María Laura Rojas ◽  
Mariano Matías Cruz del Puerto ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Bewo Cells ◽  
Cycle Arrest

scholarly journals Sonic Hedgehog Opposes Epithelial Cell Cycle Arrest

1999 ◽  
Vol 147 (1) ◽  
pp. 71-76 ◽  
Author(s):  
Hongran Fan ◽  
Paul A. Khavari
Keyword(s):  
Cell Cycle ◽  
Epithelial Cell ◽  
Cell Cycle Arrest ◽  
Sonic Hedgehog ◽  
Growth Arrest ◽  
Epidermal Hyperplasia ◽  
Shh Pathway ◽  
Cycle Arrest ◽  
Pathway Activation

Stratified epithelium displays an equilibrium between proliferation and cell cycle arrest, a balance that is disrupted in basal cell carcinoma (BCC). Sonic hedgehog (Shh) pathway activation appears sufficient to induce BCC, however, the way it does so is unknown. Shh-induced epidermal hyperplasia is accompanied by continued cell proliferation in normally growth arrested suprabasal cells in vivo. Shh-expressing cells fail to exit S and G2/M phases in response to calcium-induced differentiation and also resist exhaustion of replicative growth capacity. In addition, Shh blocks p21CIP1/WAF1-induced growth arrest. These data indicate that Shh promotes neoplasia by opposing normal stimuli for epithelial cell cycle arrest.

The C. elegans homolog of the Evi1 proto-oncogene, egl-43, coordinates G1 cell cycle arrest with pro-invasive gene expression during anchor cell invasion

2019 ◽  
Author(s):  
Ting Deng ◽  
Michael Daube ◽  
Alex Hajnal ◽  
Evelyn Lattmann
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Cell Invasion ◽  
C Elegans ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Anchor Cell

AbstractCell invasion allows cells to migrate across compartment boundaries formed by basement membranes. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells.Anchor cell (AC) invasion in C. elegans is an excellent in vivo model to study the regulation of cell invasion during development. Here, we have examined the function of egl-43, the homolog of the human Evi1 proto-oncogene (also called MECOM), in the invading AC. egl-43 plays a dual role in this process, firstly by imposing a G1 cell cycle arrest to prevent AC proliferation, and secondly, by activating pro-invasive gene expression. We have identified the AP-1 transcription factor fos-1 and the Notch homolog lin-12 as critical egl-43 targets. A positive feedback loop between fos-1 and egl-43 induces pro-invasive gene expression in the AC, while repression of lin-12 Notch expression by egl-43 ensures the G1 cell cycle arrest necessary for invasion. Reducing lin-12 levels in egl-43 depleted animals restored the G1 arrest, while hyperactivation of lin-12 signaling in the differentiated AC was sufficient to induce proliferation.Taken together, our data have identified egl-43 Evi1 as a critical factor coordinating cell invasion with cell cycle arrest.Author summaryCells invasion is a fundamental biological process that allows cells to cross compartment boundaries and migrate to new locations. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells.We have investigated how a specialized cell in the Nematode C. elegans, the so-called anchor cell, can invade into an adjacent epithelium. Our work has identified an oncogenic transcription factor that controls the expression of specific target genes necessary for cell invasion, and at the same time inhibits the proliferation of the invading anchor cell.These findings shed light on the mechanisms, by which cells decide whether to proliferate or invade.

scholarly journals The Histone Code of Senescence

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 466 ◽  
Author(s):  
Harikrishnareddy Paluvai ◽  
Eros Di Giorgio ◽  
Claudio Brancolini
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cellular Response ◽  
Premature Aging ◽  
Physiological Processes ◽  
Cycle Arrest ◽  
Damage Response ◽  
Permanent Cell ◽  
Second Wave

Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.

scholarly journals Notch Signaling and Developmental Cell-Cycle Arrest in Drosophila Polar Follicle Cells

2009 ◽  
Vol 20 (24) ◽  
pp. 5064-5073 ◽  
Author(s):  
Li-Fang Shyu ◽  
Jianjun Sun ◽  
Hui-Min Chung ◽  
Yi-Chun Huang ◽  
Wu-Min Deng
Keyword(s):  
Cell Cycle ◽  
Notch Signaling ◽  
Cell Cycle Arrest ◽  
Developmental Regulation ◽  
Cell Types ◽  
Follicle Cells ◽  
Cycle Arrest ◽  
G2 Phase ◽  
G2 Cell Cycle Arrest ◽  
Regulation Of Cell Cycle

Temporal and spatial regulation of cell division is critical for proper development of multicellular organisms. An important aspect of this regulation is cell-cycle arrest, which in many cell types is coupled with differentiated status. Here we report that the polar cells—a group of follicle cells differentiated early during Drosophila oogenesis—are arrested at G2 phase and can serve as a model cell type for investigation of developmental regulation of cell-cycle arrest. On examining the effects of String, a mitosis-promoting phosphatase Cdc25 homolog, and Notch signaling in polar cells, we found that misexpression of String can trigger mitosis in existing polar cells to induce extra polar cells. Normally, differentiation of the polar cells requires Notch signaling. We found that the Notch-induced extra polar cells arise through recruitment of the neighboring cells rather than promotion of proliferation, and they are also arrested at G2 phase. Notch signaling is probably involved in down-regulating String in polar cells, thus inducing the G2 cell-cycle arrest.

A novel nucleolar protein, PAPA-1, induces growth arrest as a result of cell cycle arrest at the G1 phase

Gene ◽  
2004 ◽  
Vol 340 (1) ◽  
pp. 83-98 ◽  
Author(s):  
Taruho S. Kuroda ◽  
Hiroshi Maita ◽  
Takanori Tabata ◽  
Takahiro Taira ◽  
Hirotake Kitaura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Growth Arrest ◽  
Nucleolar Protein ◽  
G1 Phase ◽  
Cycle Arrest
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