| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Center for Cell Signaling, Departments of 2 Pathology and 3 Chemistry, and 4 Microbiology, University of Virginia, Charlottesville, Virginia
Requests for reprints: Jeffrey A. Smith, Center for Cell Signaling, University of Virginia Health Science Center, Box 800577, Hospital West, 7041 Multistory Building, Charlottesville, VA 22908-0577. Phone: 434-924-1152; Fax: 434-924-1236; E-mail: jas8j{at}virginia.edu.
p90 ribosomal S6 kinase (RSK) is an important downstream effector of mitogen-activated protein kinase, but its biological functions are not well understood. We have now identified the first small-molecule, RSK-specific inhibitor, which we isolated from the tropical plant Forsteronia refracta. We have named this novel inhibitor SL0101. SL0101 shows remarkable specificity for RSK. The major determinant of SL0101-binding specificity is the unique ATP-interacting sequence in the amino-terminal kinase domain of RSK. SL0101 inhibits proliferation of the human breast cancer cell line MCF-7, producing a cell cycle block in G1 phase with an efficacy paralleling its ability to inhibit RSK in intact cells. RNA interference of RSK expression confirmed that RSK regulates MCF-7 proliferation. Interestingly, SL0101 does not alter proliferation of a normal human breast cell line MCF-10A, although SL0101 inhibits RSK in these cells. We show that RSK is overexpressed in 
50% of human breast cancer tissue samples, suggesting that regulation of RSK has been compromised. Thus, we show that RSK has an unexpected role in proliferation of transformed cells and may be a useful new target for chemotherapeutic agents. SL0101 will provide a powerful new tool to dissect the molecular functions of RSK in cancer cells.
Key Words: ribosomal S6 kinase • signal transduction • small-molecule kinase inhibitor • cancer
This article has been cited by other articles:
|
|
 |
|
  J. M. Flynn, D. A. Lannigan, D. E. Clark, M. H. Garner, and P. R. Cammarata RNA suppression of ERK2 leads to collapse of mitochondrial membrane potential with acute oxidative stress in human lens epithelial cells Am J Physiol Endocrinol Metab, March 1, 2008; 294(3): E589 - E599. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Kuang, Q. Tang, G. G. Maul, and F. Zhu Activation of p90 Ribosomal S6 Kinase by ORF45 of Kaposi's Sarcoma-Associated Herpesvirus and Its Role in Viral Lytic Replication J. Virol., February 15, 2008; 82(4): 1838 - 1850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-Q. Dai, X.-J. Zhu, F.-Q. Liu, J.-H. Xiang, H. Nagasawa, and W.-J. Yang Involvement of p90 Ribosomal S6 Kinase in Termination of Cell Cycle Arrest during Development of Artemia-encysted Embryos J. Biol. Chem., January 18, 2008; 283(3): 1705 - 1712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Vaidyanathan, J. Opoku-Ansah, S. Pastorino, H. Renganathan, M. L. Matter, and J. W. Ramos ERK MAP kinase is targeted to RSK2 by the phosphoprotein PEA-15 PNAS, December 11, 2007; 104(50): 19837 - 19842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ikuta, M. Kornienko, N. Byrne, J. C. Reid, S. Mizuarai, H. Kotani, and S. K. Munshi Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors Protein Sci., December 1, 2007; 16(12): 2626 - 2635. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Y. Cho, K. Yao, H.-G. Kim, B. S. Kang, D. Zheng, A. M. Bode, and Z. Dong Ribosomal S6 Kinase 2 Is a Key Regulator in Tumor Promoter Induced Cell Transformation Cancer Res., September 1, 2007; 67(17): 8104 - 8112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Malo, L. Li, and L. Fliegel Mitogen-activated Protein Kinase-dependent Activation of the Na+/H+ Exchanger Is Mediated through Phosphorylation of Amino Acids Ser770 and Ser771 J. Biol. Chem., March 2, 2007; 282(9): 6292 - 6299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Cuello, A. K. Snabaitis, M. S. Cohen, J. Taunton, and M. Avkiran Evidence for Direct Regulation of Myocardial Na+/H+ Exchanger Isoform 1 Phosphorylation and Activity by 90-kDa Ribosomal S6 Kinase (RSK): Effects of the Novel and Specific RSK Inhibitor fmk on Responses to {alpha}1-Adrenergic Stimulation Mol. Pharmacol., March 1, 2007; 71(3): 799 - 806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Chrestensen, J. K. Shuman, A. Eschenroeder, M. Worthington, H. Gram, and T. W. Sturgill MNK1 and MNK2 Regulation in HER2-overexpressing Breast Cancer Lines J. Biol. Chem., February 16, 2007; 282(7): 4243 - 4252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Godeny and P. P. Sayeski ERK1/2 regulates ANG II-dependent cell proliferation via cytoplasmic activation of RSK2 and nuclear activation of elk1 Am J Physiol Cell Physiol, December 1, 2006; 291(6): C1308 - C1317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Hauge and M. Frodin RSK and MSK in MAP kinase signalling. J. Cell Sci., August 1, 2006; 119(Pt 15): 3021 - 3023. [Full Text] [PDF]
|
|
|
|
|
|
A. A. Troussard, P. C. McDonald, E. D. Wederell, N. M. Mawji, N. R. Filipenko, K. A. Gelmon, J. E. Kucab, S. E. Dunn, J. T. Emerman, M. B. Bally, et al. Preferential Dependence of Breast Cancer Cells versus Normal Cells on Integrin-Linked Kinase for Protein Kinase B/Akt Activation and Cell Survival Cancer Res., January 1, 2006; 66(1): 393 - 403. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
