title: Cytosolic p21Waf1/Cip1 increases cell cycle transit in vascular smooth muscle cells.
abstract: The intracellular localization of signaling proteins is critical in directing their interactions with both upstream and downstream signaling cascade components. While initially described as a cyclin kinase inhibitor, p21Waf1/Cip1 has since been shown to have bimodal effects on cell cycle progression and cell proliferation, and evidence is emerging that intracellular localization of this protein plays a role in directing its signaling properties by dictating its interactions with downstream molecules. Since we have previously demonstrated a pro-apoptotic and cell cycle inhibitory effect of p21 attenuation after transfection of antisense p21 oligodeoxynucleotides (ODN) in several cell lines, we asked whether cytosolic p21 mediates a positive effect on vascular smooth muscle (VSM) cell cycle transit. We now show that transfection of a nuclear-localization signal deficient (DeltaNLS) p21 construct into VSM cells results in increased cytosolic levels of p21 and causes increased cell cycle transit as measured by [3H]thymidine incorporation. Thus, at least in VSM cells, cytosolic localization of p21 is a means by which this signaling protein transmits pro-mitogenic signals to the proteins responsible for G1/S transition. Furthermore, compartmentalization of p21 may help explain the biphasic nature of p21 in a variety of cell types and may lead to therapeutic advances directed at modulating pathologic cell growth in vascular diseases and cancer.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dong
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Chi
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.forename: Yaping
authors.initials: Y
authors.lastname: Fan
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D002451:Cell Compartmentation / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics; D051381:Rats
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019913:Nuclear Localization Signals