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The Rho GTPase effector ROCK regulates Cyclin A, Cyclin D1, and p27Kip1 levels by distinct mechanisms

The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom.
Molecular and Cellular Biology (Impact Factor: 5.04). 07/2006; 26(12):4612-27. DOI: 10.1128/MCB.02061-05
Source: PubMed

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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Available from: Daniel Croft, Apr 16, 2014
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    • "Inhibition of ROCK1 resulted in a decreased proliferation, whereas inhibition of ROCK2 had the opposite effect, significantly enhancing proliferation relative to the control cells and regulating cyclin D1, whose role is also apparent in fibroblasts [22], corneal epithelial cells, and hepatic stellate cells [23, 24], to mediate the canonical Wnt/TCF pathways involving β-catenin [25, 26]. In contrast to the opposing effects of the ROCKs described here, only ROCK2 was involved in cell proliferation changes in SH-SY5Y cells [27], indicating different pathways among cell lines. "
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    • "As described above, P61A6 induces decreased levels of cyclin D1 together with increased G1 and decreased proliferation. A number of studies in lung cancer cells suggest that RhoA plays important roles in cyclin D1 and cell cycle progression [25,26]. To rigorously test the hypothesis that RhoA is a key target of the growth inhibitory effects of P61A6, we transfected H358 cells with the wild type RhoA (3xHA-RhoA) or a mutant form of RhoA, RhoA-F (3xHA-RhoA-F), which can be farnesylated instead of geranylgeranylated, because the C-terminal leucine has been changed to serine. "
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    • "For example, polyploidization naturally occurs in megakaryocytes due to an incomplete mitosis, which is related to a partial defect in Rho-ROCK activation, and leads to an abnormal contractile ring lacking myosin IIA (Lordier et al. 2008). Moreover, Rho-ROCK signaling increases cyclin D1 and Cip1 protein levels, stimulating G1/S cell cycle progression (Croft and Olson 2006). Despite a high degree of homology between the two ROCKs, as well as the fact that they share several common substrates, studies have clearly shown that the two ROCK isoforms also have distinct and non-redundant functions. "
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