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PMID: 16227603 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, P.H.S.

Pak4 induces premature senescence via a pathway requiring p16INK4/p19ARF and mitogen-activated protein kinase signaling.

Molecular and cellular biology ·Vol. 25 ·No. 21 ·2005-11-00 ·Pages 9532-42

Cammarano MS, Nekrasova T, Noel B, Minden A

Abstract

Exposure of primary cells to mitogenic stimuli or oncogenes often causes them to undergo premature senescence. This is most likely a protective function that prevents uncontrolled proliferation. Pak4 is a target for the Rho GTPase Cdc42. Pak4 is overexpressed in human tumor cell lines, and it is the only member of the Pak family that is highly transforming in immortalized fibroblasts. Here we show that in primary fibroblasts, activated Pak4 inhibits cell proliferation and promotes premature senescence. Furthermore, Pak4 expression levels are upregulated in response to stimuli that promote senescence. Pak4-induced arrest appears to be mediated by a pathway that requires the ERK mitogen-activated protein kinase, as well as the cell cycle inhibitors p16(INK4) and p19(ARF). These new results describing a role for Pak4 in senescence are important for understanding why this protein is associated with cancer and how it promotes transformation in immortalized cells.

MeSH Terms
Animals Cell Proliferation Cell Transformation, Neoplastic Cells, Cultured Cellular Senescence/physiology Cyclin-Dependent Kinase Inhibitor p16/genetics,metabolism Extracellular Signal-Regulated MAP Kinases/metabolism Fibroblasts/physiology Humans MAP Kinase Signaling System/physiology Mice Protein Serine-Threonine Kinases/genetics,physiology Tumor Suppressor Protein p14ARF/genetics,metabolism Up-Regulation p21-Activated Kinases
Chemicals
Cdkn2a protein, mouse Cyclin-Dependent Kinase Inhibitor p16 Tumor Suppressor Protein p14ARF Pak4 protein, mouse Protein Serine-Threonine Kinases p21-Activated Kinases Extracellular Signal-Regulated MAP Kinases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Cammarano Marta S
Columbia University, Biological Sciences MC 2460, Sherman Fairchild Center, Room 813, 1212 Amsterdam Ave., New York, NY 10027, USA.
Nekrasova Tanya
Noel Beatrice
Minden Audrey
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.21.9532-9542.2005
Published
2005-11-00
Pages
9532-42
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1265798
Subset
IM
Grants
NCI NIH HHS · R01 CA076342 · United States
NCI NIH HHS · CA 76342 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.21.9532-9542.2005 PMC Full Text View journal details
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