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Molecular and Cellular Biology, October 2000, p. 7259-7272, Vol. 20, No. 19
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

SSeCKS, a Major Protein Kinase C Substrate with Tumor Suppressor Activity, Regulates G1right-arrow S Progression by Controlling the Expression and Cellular Compartmentalization of Cyclin D

Xueying Lin,1,dagger Peter Nelson,2 and Irwin H. Gelman2,3,*

Departments of Microbiology1 and Medicine2 and Ruttenberg Cancer Center,3 Mount Sinai School of Medicine, New York, New York 10029-6574

Received 8 February 2000/Returned for modification 20 June 2000/Accepted 5 July 2000

SSeCKS, first isolated as a G1right-arrowS inhibitor that is downregulated in src- and ras-transformed cells, is a major cytoskeleton-associated PKC substrate with tumor suppressor and kinase-scaffolding activities. Previous attempts at constitutive expression resulted in cell variants with truncated ectopic SSeCKS products. Here, we show that tetracycline-regulated SSeCKS expression in NIH 3T3 cells induces G1 arrest marked by extracellular signal-regulated kinase 2-dependent decreases in cyclin D1 expression and pRb phosphorylation. Unexpectedly, the forced reexpression of cyclin D1 failed to rescue SSeCKS-induced G1 arrest. Confocal microscopy analysis revealed cytoplasmic colocalization of cyclin D1 with SSeCKS. Because the SSeCKS gene encodes two potential cyclin-binding motifs (CY) flanking major in vivo protein kinase C (PKC) phosphorylation sites (Ser507/515), we addressed whether SSeCKS encodes a phosphorylation-dependent cyclin scaffolding function. Bacterially expressed SSeCKS-CY bound cyclins D1 and E, whereas Kright-arrowS mutations within either CY motif ablated binding. Activation of PKC in vivo caused a rapid translocation of cyclin D1 to the nucleus. Cell permeable, penetratin-linked peptides encoding wild-type SSeCKS-CY, but not Kright-arrowS or phospho-Ser507/515 variants, released cyclin D1 from its cytoplasmic sequestration and induced higher saturation density in cyclin D1-overexpressor cells or rat embryo fibroblasts. Our data suggest that SSeCKS controls G1right-arrowS progression by regulating the expression and localization of cyclin D1. These data suggest that downregulation of SSeCKS in tumor cells removes gating checkpoints for saturation density, an effect that may promote contact independence.

* Corresponding author. Mailing address: Department of Medicine and Ruttenberg Cancer Center, Mount Sinai School of Medicine, Box 1090, One Gustave L. Levy Place, New York, NY 10029-6574. Phone: (212) 241-3749. Fax: (212) 828-4202. E-mail: irwin.gelman{at}mssm.edu.

dagger Present address: Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215.

Molecular and Cellular Biology, October 2000, p. 7259-7272, Vol. 20, No. 19
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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