The ability to degrade extracellular matrix is critical for tumor cells to invade and metastasize. Recent studies show that tumor cells utilize specialized actin-based membrane protrusions termed invadopodia to perform matrix degradation. Invadopodia provide an elegant way for tumor cells to precisely couple focal matrix degradation with directional movement. Here we discuss several key components and regulators of invadopodia that have been uniquely implicated in tumor invasion and metastasis. Furthermore, we discuss existing and new therapeutic opportunities to target invadopodia for anti-metastasis treatment.

The p53 tumor suppressor restricts tumorigenesis through the transcriptional activation of target genes involved in cell-cycle arrest and apoptosis. Here, we identify Prl-3 (phosphatase of regenerating liver-3) as a p53-inducible gene. Whereas previous studies implicated Prl-3 in metastasis because of its overexpression in metastatic human colorectal cancer and its ability to promote invasiveness and motility, we demonstrate here that Prl-3 is an important cell-cycle regulator. Consistent with a role in DNA damage-induced cell-cycle arrest, Prl-3 overexpression induces G(1) arrest downstream of p53 by triggering a PI3K-Akt-activated negative feedback loop. Surprisingly, attenuation of Prl-3 expression also elicits an arrest response, suggesting that basal level Prl-3 expression is pivotal for normal cell-cycle progression. Our findings highlight key dose-dependent functions of Prl-3 in both positive and negative regulation of cell-cycle progression and provide insight into Prl-3's role in cancer progression.

p53 plays a central role in neuronal cell death resulting from acute injury or disease. To define the pathway by which p53 triggers apoptosis, we used microarray analysis to identify p53 target genes specifically upregulated during apoptosis but not cell cycle arrest. This analysis identified a small subset of targets highly selective for the p53 apoptotic response, including Siva, a proapoptotic protein whose function is not well understood. Siva's expression pattern suggests that it plays an instructive role in apoptosis, and accordingly, we demonstrate that Siva is essential for p53-dependent apoptosis in cerebellar granule neurons. In addition, we determine that endogenous Siva is associated with the plasma membrane and that Caspase-8 and Bid are important for neuronal apoptosis. Our studies highlight the participation of membrane signaling events in p53's apoptotic program in primary neurons and have significant implications for understanding the mechanisms underlying pathogenesis after neuronal injury and in neurodegenerative diseases.

Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC) or Hay-Wells Syndrome is an autosomal dominant disorder characterized by a variety of phenotypes in ectodermal derivatives, including severe skin erosions, ankyloblepharon, coarse and wiry hair, scalp dermatitis, and dystrophic nails. AEC is caused by mutations in the gene encoding the TP63 transcription factor, specifically in the Sterile Alpha Motif (SAM) domain. The exact mechanism, however, by which these specific TP63 mutations lead to the observed spectrum of phenotypes is unclear. Analysis of individual TP63 target genes provides a means to understand specific aspects of the phenotypes associated with AEC. PERP is a TP63 target critical for cell-cell adhesion due to its participation in desmosomal adhesion complexes. As PERP null mice display symptoms characteristic of ectodermal dysplasia syndromes, we hypothesized that PERP dysfunction might contribute to AEC. Using luciferase reporter assays, we demonstrate here that PERP induction is in fact compromised with some, but not all, AEC-patient derived TP63 mutants. Through analysis of skin biopsies from AEC patients, we show further that a subset of these display aberrant PERP expression, suggesting the possibility that PERP dysregulation is involved in the pathogenesis of this disease. These findings demonstrate that distinct AEC TP63 mutants can differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. Elucidating how specific TP63 target genes contribute to the pathogenesis of AEC will ultimately help design novel approaches to diagnose and treat AEC.

The contribution of transcriptional activation to the p53 effector functions critical for tumor suppression, apoptosis and cellular senescence, remains unclear because of p53's ability to regulate diverse cellular processes in a transactivation-independent manner. Dissociating the importance of transactivation from other p53 functions, including regulating transcriptional repression, DNA replication, homologous recombination, centrosome duplication, and mitochondrial function, has been difficult because of overlapping motifs for these functions in the amino terminus. To determine the relative contribution of these activities and transactivation to p53 function, we generated knockin mice expressing a p53 mutant lacking domains involved in these transactivation-independent functions, while remaining competent for transactivation through fusion to the Herpes Simplex Virus VP16 transactivation domain. This chimeric mutant, termed p53 VP16 , robustly activates the transcription of a range of p53 targets involved in both apoptosis and senescence. Intriguingly, despite being transactivation-competent, this chimeric protein shows selectivity in p53 effector function in mouse fibroblasts, with a capacity to trigger senescence but not apoptosis under a variety of conditions. Our study highlights the central role of p53 transactivation for senescence while suggesting that transactivation is insufficient for apoptosis, and provides insight into the mechanisms by which p53 serves as a tumor suppressor. mouse model ͉ transactivation ͉ tumor suppression