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

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.

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The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21CIP1/Waf1

Oncogene ◽

10.1038/sj.onc.1205842 ◽

2002 ◽

Vol 21 (39) ◽

pp. 6123-6131 ◽

Cited By ~ 36

Author(s):

Vishwanie Budram-Mahadeo ◽

Peter J Morris ◽

David S Latchman

Keyword(s):

Cell Cycle ◽

Transcription Factor ◽

Cell Cycle Arrest ◽

Target Genes ◽

Cycle Arrest ◽

Genes Encoding ◽

Apoptotic Effect ◽

P53 Target Genes

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Propylparaben induces apoptotic cell death in human placental BeWo cells via cell cycle arrest and enhanced caspase-3 activity

Molecular & Cellular Toxicology ◽

10.1007/s13273-019-00062-9 ◽

2019 ◽

Vol 16 (1) ◽

pp. 83-92 ◽

Cited By ~ 3

Author(s):

Mi Jin Kim ◽

Chul-Hong Kim ◽

Mi-Jin An ◽

Ju-Hyun Lee ◽

Geun-Seup Shin ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Cycle Arrest ◽

Caspase 3 ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Bewo Cells ◽

Cycle Arrest

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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

10.1101/802355 ◽

2019 ◽

Cited By ~ 1

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.

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