Protein kinase CK1alphaLS promotes vascular cell proliferation and intimal hyperplasia.
Protein kinase CK1alpha regulates several fundamental cellular processes including proliferation and differentiation. Up to four forms of this kinase are expressed in vertebrates resulting from alternative splicing of exons; these exons encode either the L-insert located within the catalytic domain or the S-insert located at the C terminus of the protein. Whereas the L-insert is known to target the kinase to the nucleus, the functional significance of nuclear CK1alphaLS has been unclear. Here we demonstrate that selective L-insert-targeted short hairpin small interfering RNA-mediated knockdown of CK1alphaLS in human vascular endothelial cells and vascular smooth muscle cells impairs proliferation and abolishes hydrogen peroxide-stimulated proliferation of vascular smooth muscle cells, with the cells accumulating in G(0)/G(1). In addition, selective knockdown of CK1alphaLS in cultured human arteries inhibits vascular activation, preventing smooth muscle cell proliferation, intimal hyperplasia, and proteoglycan deposition. Knockdown of CK1alphaLS results in the harmonious down-regulation of its target substrate heterogeneous nuclear ribonucleoprotein C and results in the altered expression or alternative splicing of key genes involved in cellular activation including CXCR4, MMP3, CSF2, and SMURF1. Our results indicate that the nuclear form of CK1alpha in humans, CK1alphaLS, plays a critical role in vascular cell proliferation, cellular activation, and hydrogen peroxide-mediated mitogenic signal transduction.
Panchenko
Mikhail P
MP
Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Siddiquee
Zakir
Z
Dombkowski
David M
DM
Alekseyev
Yuriy O
YO
Lenburg
Marc E
ME
Walker
Jennifer D
JD
Macgillivray
Thomas E
TE
Preffer
Frederic I
FI
Stone
James R
JR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D048128:Casein Kinase Ialpha / Q000378:metabolism*; D002452:Cell Count; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013895:Thoracic Arteries / Q000378:metabolism / Q000473:pathology; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology*
D048128:Casein Kinase Ialpha