Published March 24, 2014
Text by Ben Short
[email protected]
In Focus
p53 cuts off invading cells
The tumor suppressor limits cell invasion by inducing a mitochondrial protease to cleave
the actin cytoskeleton.
FOCAL POINT
he tumor suppressor p53 does all
(Bottom left) Shota Yamauchi, (top row, left to right) Keiko
Kawauchi, Yan Yan Hou, Alvin Kunyao Guo, and colleagues
it can to prevent oncogenes from
(not pictured) investigate how the tumor suppressor p53
inducing tumorigenesis, killing
limits cancer cell invasion. In the absence of p53 (bottom
defective cells or pushing them into senescenter), fibroblasts expressing oncogenic Ras form numerous
cence. Sometimes, oncogenes manage to
focal adhesions (red) containing phosphorylated p130Cas
initiate tumor development in the presence
(green), which stimulates lamellipodial protrusion and cell
invasion. In contrast, transformed fibroblasts expressing
of p53, but, even then, the tumor suppresp53 (bottom right) have few focal adhesions and low
sor doesn’t give up and focuses its efforts
levels of p130Cas phosphorylation and therefore limited
instead on limiting the tumor’s ability to
invasiveness. p53 down-regulates p130Cas phosphorylation
invade and metastasize (1). Yamauchi et
by promoting the activation of a mitochondrial protease,
al. reveal that one way p53 accomplishes
HtrA2, that, upon its release into the cytosol, cleaves ␤-actin
to lower F-actin levels and inhibit p130Cas signaling.
this is by activating a mitochondrial protease
TOP PHOTO COURTESY OF STEVEN WOLF; YAMAUCHI
to cleave ␤-actin and restrict the formation PHOTO COURTESY OF THE AUTHOR
of invasive membrane protrusions (2).
“Most research has focused on how filaments with jasplakinolide had the cleave ␤-actin upon its release into
p53 prevents metastasis by regulating opposite effect. In the presence of wild- the cytosol after mitochondrial fragmentaepithelial-to-mesenchymal transitions,” ex- type p53, oncogenic Ras lowered F-actin tion. The MAP kinase p38 is critical to
plains Keiko Kawauchi from the Mechano- levels by inducing the proteolytic cleav- this activation step. “p53 promotes the
biology Institute at the National Univer- age of ␤-actin, thereby reducing p130Cas translocation of p38 into mitochondria so
sity of Singapore. In contrast, she says, phosphorylation. Ras-transformed fibro- that the MAP kinase can phosphorylate
little is known about how p53 affects the blasts that either lacked p53 or expressed and activate HtrA2,” Kawauchi explains.
cytoskeletal processes that drive cell inva- a dominant-negative version of the tumor
p53 promoted p38’s translocation into
sion. Kawauchi and colleagues, led by suppressor showed no such decrease in mitochondria by reducing the inner memShota Yamauchi, therefore compared Ras- F-actin levels or p130Cas phosphorylation.
brane potential of mitochondria near the
The researchers then investigated which periphery of Ras-transformed fibroblasts.
transformed fibroblasts with and without
wild-type p53 (2). Compared with p53- protease was targeting ␤-actin. “Caspase-3 Ras induced p53’s accumulation in the
null cells, transformed fibroblasts express- and the mitochondrial protease HtrA2 have cytoplasm, allowing the tumor suppressor
ing p53 were less invasive and formed been shown to cleave ␤-actin,” says to stimulate p38 import, HtrA2 activation
fewer focal adhesions to the extracellular Kawauchi. “Caspase-3 wasn’t activated by and, after Ras-induced mitochondrial
matrix. p130Cas, a focal adhesion signal- Ras transformation, so we focused on fission, ␤-actin cleavage. “The decrease
HtrA2. Knocking down or in F-actin suppresses p130Cas signaling,”
ing protein that promotes
inhibiting this protease sup- says Kawauchi, “so actin remodeling is
the formation of lamellipo“Actin
pressed ␤-actin cleavage a signal that prevents cell invasion.”
dial membrane protrusions
and enhanced the invasion
and cancer cell invasion (3),
Kawauchi and colleagues now want to
remodeling
of Ras-transformed, p53- investigate how p53 reduces the membrane
was less phosphorylated in
is a signal
positive fibroblasts.”
p53-positive cells, indicatpotential of peripheral mitochondria. “How
that prevents
HtrA2 normally resides does p53 regulate local changes in mitoing that the tumor suppressor limits invasion by
cell invasion.” in the intermembrane space chondrial potential? It will be important
of mitochondria, but p53 for us to find out,” she says.
down-regulating the activity
overexpression can induce
of this protein. Indeed,
knocking down p130Cas suppressed the the protease’s release into the cytosol (5). 1. Muller, P.A., et al. 2011. J. Cell Biol. 192:209–218.
invasion of Ras-transformed fibroblasts By stimulating mitochondrial fission, 2. Yamauchi, S., et al. 2014. J. Cell Biol. http://
dx.doi.org/10.1083/jcb.201309107.
however, oncogenic Ras induced HtrA2’s
lacking p53.
3.
Defi
lippi, P., et al. 2006. Trends Cell Biol.
Yamauchi et al. found that, as for other release even in cells lacking p53. What
16:257–263.
focal adhesion proteins (4), p130Cas then is the role of p53? The researchers
phosphorylation was enhanced by actin found that the tumor suppressor lowers 4. Parsons, J.T., et al. 2010. Nat. Rev. Mol. Cell Biol.
11:633–643.
polymerization. The actin-depolymerizing actin levels and inhibits cell invasion by
5. Marabese, M., et al. 2008. Cell Death Differ.
drug cytochalasin D reduced p130Cas promoting HtrA2’s activation inside mito15:849–858.
phosphorylation, whereas stabilizing actin chondria so that the protease can efficiently
T
Downloaded from on June 17, 2017
In Focus • THE JOURNAL OF CELL BIOLOGY
1079