Affiliation:
1. The Beatson Institute for Cancer Research, Glasgow G61 1BD, United
Kingdom
Abstract
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 G
1
/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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology