TY - JOUR
T1 - Cyclin D1 regulates cellular migration through the inhibition of thrombospondin 1 and ROCK signaling
AU - Li, Zhiping
AU - Wang, Chenguang
AU - Jiao, Xuanmao
AU - Lu, Yinan
AU - Fu, Maofu
AU - Quong, Andrew A.
AU - Dye, Chip
AU - Yang, Jianguo
AU - Dai, Maozheng
AU - Ju, Xiaoming
AU - Zhang, Xueping
AU - Li, Anping
AU - Burbelo, Peter
AU - Stanley, E. Richard
AU - Pestell, Richard G.
PY - 2006/6
Y1 - 2006/6
N2 - Cyclin D1 is overexpressed in human tumors, correlating with cellular metastasis, and is induced by activating Rho GTPases. Herein, cyclin D1-deficient mouse embryo fibroblasts (MEFs) exhibited increased adhesion and decreased motility compared with wild-type MEFs. Retroviral transduction of cyclin D1 reversed these phenotypes. Mutational analysis of cyclin D1 demonstrated that its effects on cellular adhesion and migration were independent of the pRb and p160 coactivator binding domains. Genomewide expression arrays identified a subset of genes regulated by cyclin D1, including Rho-activated kinase II (ROCKII) and thrombospondin 1 (TSP-1). cyclin D1 -/- cells showed increased Rho GTP and ROCKII activity and signaling, with increased phosphorylation of LIM kinase, cofilin (Ser3), and myosin light chain 2 (Thr18/Ser19). Cyclin D1 repressed ROCKII and TSP-1 expression, and the migratory defect of cyclin D1-/- cells was reversed by ROCK inhibition or TSP-1 immunoneutralizing antibodies, cyclin E knockin to the cyclin D1-/- MEFs rescued the DNA synthesis defect of cyclin D1 -/- MEFs but did not rescue either the migration defect or the abundance of ROCKII. Cyclin D1 promotes cellular motility through inhibiting ROCK signaling and repressing the metastasis suppressor TSP-1.
AB - Cyclin D1 is overexpressed in human tumors, correlating with cellular metastasis, and is induced by activating Rho GTPases. Herein, cyclin D1-deficient mouse embryo fibroblasts (MEFs) exhibited increased adhesion and decreased motility compared with wild-type MEFs. Retroviral transduction of cyclin D1 reversed these phenotypes. Mutational analysis of cyclin D1 demonstrated that its effects on cellular adhesion and migration were independent of the pRb and p160 coactivator binding domains. Genomewide expression arrays identified a subset of genes regulated by cyclin D1, including Rho-activated kinase II (ROCKII) and thrombospondin 1 (TSP-1). cyclin D1 -/- cells showed increased Rho GTP and ROCKII activity and signaling, with increased phosphorylation of LIM kinase, cofilin (Ser3), and myosin light chain 2 (Thr18/Ser19). Cyclin D1 repressed ROCKII and TSP-1 expression, and the migratory defect of cyclin D1-/- cells was reversed by ROCK inhibition or TSP-1 immunoneutralizing antibodies, cyclin E knockin to the cyclin D1-/- MEFs rescued the DNA synthesis defect of cyclin D1 -/- MEFs but did not rescue either the migration defect or the abundance of ROCKII. Cyclin D1 promotes cellular motility through inhibiting ROCK signaling and repressing the metastasis suppressor TSP-1.
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U2 - 10.1128/MCB.02124-05
DO - 10.1128/MCB.02124-05
M3 - Article
C2 - 16705174
AN - SCOPUS:33646893508
SN - 0270-7306
VL - 26
SP - 4240
EP - 4256
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 11
ER -