scholarly journals Mitogen-Activated Protein Kinase Hog1 Mediates Adaptation to G1 Checkpoint Arrest during Arsenite and Hyperosmotic Stress

2008 ◽  
Vol 7 (8) ◽  
pp. 1309-1317 ◽  
Author(s):  
Iwona Migdal ◽  
Yulia Ilina ◽  
Markus J. Tamás ◽  
Robert Wysocki
Keyword(s):  
Cell Cycle ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
Kinase Inhibitor ◽  
Hyperosmotic Stress ◽  
Mitogen Activated Protein Kinase ◽  
Hog Pathway ◽  
Cycle Arrest ◽  
Mitogen Activated Protein

ABSTRACT Cells slow down cell cycle progression in order to adapt to unfavorable stress conditions. Yeast (Saccharomyces cerevisiae) responds to osmotic stress by triggering G1 and G2 checkpoint delays that are dependent on the mitogen-activated protein kinase (MAPK) Hog1. The high-osmolarity glycerol (HOG) pathway is also activated by arsenite, and the hog1Δ mutant is highly sensitive to arsenite, partly due to increased arsenite influx into hog1Δ cells. Yeast cell cycle regulation in response to arsenite and the role of Hog1 in this process have not yet been analyzed. Here, we found that long-term exposure to arsenite led to transient G1 and G2 delays in wild-type cells, whereas cells that lack the HOG1 gene or are defective in Hog1 kinase activity displayed persistent G1 cell cycle arrest. Elevated levels of intracellular arsenite and “cross talk” between the HOG and pheromone response pathways, observed in arsenite-treated hog1Δ cells, prolonged the G1 delay but did not cause a persistent G1 arrest. In contrast, deletion of the SIC1 gene encoding a cyclin-dependent kinase inhibitor fully suppressed the observed block of G1 exit in hog1Δ cells. Moreover, the Sic1 protein was stabilized in arsenite-treated hog1Δ cells. Interestingly, Sic1-dependent persistent G1 arrest was also observed in hog1Δ cells during hyperosmotic stress. Taken together, our data point to an important role of the Hog1 kinase in adaptation to stress-induced G1 cell cycle arrest.

scholarly journals p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint

2009 ◽  
Vol 29 (16) ◽  
pp. 4341-4351 ◽  
Author(s):  
Vanesa Lafarga ◽  
Ana Cuadrado ◽  
Isabel Lopez de Silanes ◽  
Rocio Bengoechea ◽  
Oscar Fernandez-Capetillo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Γ Radiation ◽  
Cycle Arrest ◽  
Mitogen Activated Protein

ABSTRACT Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G2/M cell cycle arrest induced by DNA damage, but little is known about the role of this signaling pathway in the G1/S transition. Upregulation of the cyclin-dependent kinase inhibitor p21Cip1 is thought to make a major contribution to the G1/S cell cycle arrest induced by γ radiation. We show here that inhibition of p38 MAPK impairs p21Cip1 accumulation and, as a result, the ability of cells to arrest in G1 in response to γ radiation. We found that p38 MAPK induces p21Cip1 mRNA stabilization, without affecting its transcription or the stability of the protein. In particular, p38 MAPK phosphorylates the mRNA binding protein HuR on Thr118, which results in cytoplasmic accumulation of HuR and its enhanced binding to the p21Cip1 mRNA. Our findings help to understand the emerging role of p38 MAPK in the cellular responses to DNA damage and reveal the existence of p53-independent networks that cooperate in modulating p21Cip1 levels at the G1/S checkpoint.

scholarly journals Loss of Oncogenic H-ras-Induced Cell Cycle Arrest and p38 Mitogen-Activated Protein Kinase Activation by Disruption of Gadd45a

2003 ◽  
Vol 23 (11) ◽  
pp. 3859-3871 ◽  
Author(s):  
Dmitry V. Bulavin ◽  
Oleg Kovalsky ◽  
M. Christine Hollander ◽  
Albert J. Fornace
Keyword(s):  
Cell Cycle ◽  
Amino Acids ◽  
Protein Kinase ◽  
Cell Cycle Arrest ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Cycle Arrest ◽  
Mitogen Activated Protein ◽  
P53 Activation

ABSTRACT The activation of p53 is a guardian mechanism to protect primary cells from malignant transformation; however, the details of the activation of p53 by oncogenic stress are still incomplete. In this report we show that in Gadd45a −/− mouse embryo fibroblasts (MEF), overexpression of H-ras activates extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 kinase, and this correlates with the loss of H-ras-induced cell cycle arrest (premature senescence). Inhibition of p38 mitogen-activated protein kinase (MAPK) activation correlated with the deregulation of p53 activation, and both a p38 MAPK chemical inhibitor and the expression of a dominant-negative p38α inhibited p53 activation in the presence of H-ras in wild-type MEF. p38, but not ERK or JNK, was found in a complex with Gadd45 proteins. The region of interaction was mapped to amino acids 71 to 96, and the central portion (amino acids 71 to 124) of Gadd45a was required for p38 MAPK activation in the presence of H-ras. Our results indicate that this Gadd45/p38 pathway plays an important role in preventing oncogene-induced growth at least in part by regulating the p53 tumor suppressor.

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