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The Rho GTPase Effector ROCK Regulates Cyclin A, Cyclin D1, and p27Kip1 Levels by Distinct Mechanisms
Abstract
The members of the Rho GTPase family are well known for their regulation of actin cytoskeletal structures. In addition, they influence progression through the cell cycle. The RhoA and RhoC proteins regulate numerous effector proteins, with a central and vital signaling role mediated by the ROCK I and ROCK II serine/threonine kinases. The requirement for ROCK function in the proliferation of numerous cell types has been revealed by studies utilizing ROCK-selective inhibitors such as Y-27632. However, the mechanisms by which ROCK signaling promotes cell cycle progression have not been thoroughly characterized. Using a conditionally activated ROCK-estrogen receptor fusion protein, we found that ROCK activation is sufficient to stimulate G1/S cell cycle progression in NIH 3T3 mouse fibroblasts. Further analysis revealed that ROCK acts via independent pathways to alter the levels of cell cycle regulatory proteins: cyclin D1 and p21(Cip1) elevation via Ras and the mitogen-activated protein kinase pathway, increased cyclin A via LIM kinase 2, and reduction of p27(Kip1) protein levels. Therefore, the influence of ROCK on cell cycle regulatory proteins occurs by multiple independent mechanisms.
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Latrunculins: Novel Marine Toxins That Disrupt Microfilament Organization in Cultured Cells
Spector, I., Shochet, N. R., Kashman, Y., & Groweiss, A. (1983) · Science · doi:10.1126/science.6681676 · Cited by 750
Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis
Landis, M. W., Pawlyk, B. S., Li, T., Sicinski, P., & Hinds, P. W. (2006) · Cancer Cell · doi:10.1016/j.ccr.2005.12.019 · Cited by 329
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Rho-associated coiled-coil containing kinases (ROCK): Structure, regulation, and functions
Julian, L., & Olson, M. F. (2014) · Small GTPases · doi:10.4161/sgtp.29846 · Cited by 550
Self-citationEnhancement on Primate Corneal Endothelial Cell Survival In Vitro by a ROCK Inhibitor
Okumura, N., Ueno, M., Koizumi, N., Sakamoto, Y., Hirata, K., Hamuro, J., & Kinoshita, S. (2009) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.08-2634 · Cited by 300
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Ellenbroek, S. I. J., & Collard, J. G. (2007) · Clinical & Experimental Metastasis · doi:10.1007/s10585-007-9119-1 · Cited by 289
Rho-kinase: Regulation, (dys)function, and inhibition
Amin, E., Dubey, B. N., Zhang, S.-C., Gremer, L., Dvorsky, R., Moll, J. M., Taha, M. S., Nagel-Steger, L., Piekorz, R. P., Somlyo, A. V., et al. (2013) · bchm · doi:10.1515/hsz-2013-0181 · Cited by 176
Metadata
- Authors
- Croft, D. R., & Olson, M. F.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-06-01
- Volume
- 26
- Issue
- 12
- Pages
- 4612-4627
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- OpenAlex
- W2169328538
- Cited by
- 159
- References
- 2
- FWCI
- 4.79
- Type
- journal article
- Language
- en
- Open access
- closed
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- Croft, D. R., & Olson, M. F. (2006). The Rho GTPase Effector ROCK Regulates Cyclin A, Cyclin D1, and p27Kip1 Levels by Distinct Mechanisms. Molecular and Cellular Biology. https://doi.org/10.1128/mcb.02061-05
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