IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
artículos
Título:
p38{gamma} Promotes Breast Cancer Cell Motility and Metastasis through Regulation of RhoC GTPase, Cytoskeletal Architecture, and a Novel Leading Edge Behavior
Autor/es:
DEVIN T ROSENTHAL; HARISH IYER; SILVIA ESCUDERO; LIWEI BAO; ZHIFEN WU; ALEJANDRA C VENTURA; CELINA G KLEER; ELLEN M ARRUDA; KRISHNA GARIKIPATI; SOFIA D MERAJVER
Revista:
CANCER RESEARCH
Editorial:
AMER ASSOC CANCER RESEARCH
Referencias:
Lugar: Philadelphia; Año: 2011 vol. 71 p. 6338 - 6349
ISSN:
0008-5472
Resumen:
Understanding the molecular alterations that confer cancer cells with
motile, metastatic properties is needed to improve patient survival.
Here, we report that p38γ motogen-activated protein kinase regulates
breast cancer cell motility and metastasis, in part, by controlling
expression of the metastasis-associated small GTPase RhoC. This
p38γ-RhoC regulatory connection was mediated by a novel mechanism of
modulating RhoC ubiquitination. This relationship persisted across
multiple cell lines and in clinical breast cancer specimens. Using a
computational mechanical model based on the finite element method, we
showed that p38γ-mediated cytoskeletal changes are sufficient to control
cell motility. This model predicted novel dynamics of leading edge
actin protrusions, which were experimentally verified and established to
be closely related to cell shape and cytoskeletal morphology. Clinical
relevance was supported by evidence that elevated expression of p38γ is
associated with lower overall survival of patients with breast cancer.
Taken together, our results offer a detailed characterization of how
p38γ contributes to breast cancer progression. Herein we present a new
mechanics-based analysis of cell motility, and report on the discovery
of a leading edge behavior in motile cells to accommodate modified
cytoskeletal architecture. In summary, these findings not only identify a
novel mechanism for regulating RhoC expression but also advance p38γ as
a candidate therapeutic target. Cancer Res; 71(20); 6338-49. ©2011
AACR.