Cell Cycle Arrest Mediated by the MEK/Mitogen-Activated Protein Kinase Pathway

The mitogen-activated protein kinase (MAPK) cascade plays a crucial role in the transduction of extracellular signals into responses governing growth and differentiation. The effects of a specific inhibitor of the MAPK kinase (MEK)/MAPK pathway (PD98059) on nerve growth factor (NGF)-induced growth a...

Full description

Saved in:

Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS 1997-01, Vol.94 (2), p.448-452
Main Authors:	Pumiglia, Kevin M., Decker, Stuart J.
Format:	Article
Language:	eng
Subjects:	3T3 Cells Animals Biochemistry Biological Sciences Calcium-Calmodulin-Dependent Protein Kinases - metabolism Carrier Proteins - physiology Cation Transport Proteins CDC2-CDC28 Kinases Cell Cycle Cell growth Cell lines Cells Cellular biology Cyclin D Cyclin-Dependent Kinase 2 Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor p21 Cyclin-Dependent Kinases - metabolism Cyclins Cyclins - metabolism Enzyme Inhibitors - pharmacology Flavonoids - pharmacology MAP Kinase Kinase 1 Membrane Proteins - physiology Mice Mitogen-Activated Protein Kinase Kinases Nerve Growth Factors - physiology Neurology Oncogenes PC12 cells Phosphorylation Photoreceptors Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - metabolism Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - metabolism Proteins Proto-Oncogene Proteins Saccharomyces cerevisiae Proteins Schwann cells Signal Transduction
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The mitogen-activated protein kinase (MAPK) cascade plays a crucial role in the transduction of extracellular signals into responses governing growth and differentiation. The effects of a specific inhibitor of the MAPK kinase (MEK)/MAPK pathway (PD98059) on nerve growth factor (NGF)-induced growth arrest and inhibition of cell cycle-dependent kinases (CDKs) have been examined. Treatment of NIH 3T3 cells expressing TRKA with PD98059 dramatically reversed the complete inhibition of growth of these cells caused by NGF. PD98059 also blocked the ability of NGF to inhibit the activities of CDK4 and CDK2, while partially preventing NGF induction of p21Cip1/WAF1. To independently evaluate the involvement of the MEK/MAPK pathway in growth arrest, an inducible activated form of the Raf-1 protooncogene (Δ RAF-1:ER) was expressed in these cells. Activation of Δ RAF-1:ER resulted in a prolonged increase in MAPK activity and growth arrest of these cells, with concomitant induction of p21Cip1/WAF1 and inhibition of CDK2 activity. These effects of Δ RAF-1:ER activation were all reversed by treatment of cells with PD98059. These data indicate that in addition to functioning as a positive effector of growth, stimulation of the MEK/MAPK pathway can result in an inhibition of CDK activity and cell cycle arrest.
ISSN:	0027-8424 1091-6490