p53 cuts off invading cells

In Focus • THE JOURNAL OF CELL BIOLOGY p53 cuts off invading cells T he tumor suppressor p53 does all it can to prevent oncogenes from inducing tumorigenesis, killing defective cells or pushing them into senes-cence. Sometimes, oncogenes manage to initiate tumor development in the presence of p53, but, even then, the tumor suppressor doesn't give up and focuses its efforts instead on limiting the tumor's ability to invade and metastasize (1). Yamauchi et al. reveal that one way p53 accomplishes this is by activating a mitochondrial protease to cleave ␤-actin and restrict the formation of invasive membrane protrusions (2). " Most research has focused on how p53 prevents metastasis by regulating epithelial-to-mesenchymal transitions, " explains Keiko Kawauchi from the Mechano-biology Institute at the National University of Singapore. In contrast, she says, little is known about how p53 affects the cytoskeletal processes that drive cell invasion. Kawauchi and colleagues, led by Shota Yamauchi, therefore compared Ras-transformed fi broblasts with and without wild-type p53 (2). Compared with p53-null cells, transformed fi broblasts expressing p53 were less invasive and formed fewer focal adhesions to the extracellular matrix. p130Cas, a focal adhesion signal-ing protein that promotes the formation of lamellipo-dial membrane protrusions and cancer cell invasion (3), was less phosphorylated in p53-positive cells, indicating that the tumor suppressor limits invasion by down-regulating the activity of this protein. Indeed, knocking down p130Cas suppressed the invasion of Ras-transformed fi broblasts lacking p53. Yamauchi et al. found that, as for other focal adhesion proteins (4), p130Cas phosphorylation was enhanced by actin polymerization. The actin-depolymerizing drug cytochalasin D reduced p130Cas phosphorylation, whereas stabilizing actin filaments with jasplakinolide had the opposite effect. In the presence of wild-type p53, oncogenic Ras lowered F-actin levels by inducing the proteolytic cleav-age of ␤-actin, thereby reducing p130Cas phosphorylation. Ras-transformed fi bro-blasts that either lacked p53 or expressed a dominant-negative version of the tumor suppressor showed no such decrease in F-actin levels or p130Cas phosphorylation. The researchers then investigated which protease was targeting ␤-actin. " Caspase-3 and the mitochondrial protease HtrA2 have been shown to cleave ␤-actin, " says Kawauchi. " Caspase-3 wasn't activated by Ras transformation, so we focused on HtrA2. Knocking down or inhibiting this protease suppressed ␤-actin cleavage and enhanced the invasion of Ras-transformed, p53-positive fi broblasts. " HtrA2 normally resides in the intermembrane space of mitochondria, but p53 overexpression can induce the protease's release into the cytosol (5). By …