The transcription factor ATF-2 inhibits extracellular signal regulated kinase expression and proliferation of human cancer cells.
The mitogen activated protein kinase (MAPK) pathway is a paradigm for regulation of growth factor signaling and cellular proliferation. The MAPK pathway is a major target for signaling by growth factor receptor kinases. The MAPK pathway consists of a series of protein kinases which is activated by phosphorylation of specific amino acid residues in their regulatory domains. The MAPK family can be divided into three subgroups: the extracellular signal regulated kinases (ERKs), the stress activated protein kinase/jun N terminal kinase (SAPK/JNK), and the p38 MAPK. These kinase cascades phosphorylate transcription factor targets such as ets, c-jun, and ATF-2. Of these, little is known about the role of ATF-2 in regulation of MAPK signaling and cellular proliferation. To begin to understand this role, we overexpressed ATF-2 in a human cancer cell line. ATF-2 inhibited the G1/S phase transition of the cell cycle and decreased the proliferation rate of these cells. Decreased proliferation correlated with cell cycle independent inhibition of ERK1 expression in ATF-2 clones. Genetic and pharmacologic inhibition of ERK1 activity was sufficient to reproduce the effects of ATF-2 on cell cycle progression and proliferation. These results indicate a novel role for ATF-2 in cancer cell proliferation and suggest a potential feedback mechanism that regulates MAPK signaling.
Crowe
D L
DL
Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles 90033, USA.
Shemirani
B
B
D051698:Activating Transcription Factor 2; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002294:Carcinoma, Squamous Cell; D002453:Cell Cycle; D002455:Cell Division; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors; D016203:CDC2 Protein Kinase; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases