Tumor invasion and metastases are multifaceted processes involving adhesion, proteolytic degradation of tissue barriers, and cell migration. Induction of cellular motility has been demonstrated with multiple growth factors and in some instances has been linked to the activation of phosphatidylinositol (PI) 1 3-kinase (1-4). PI 3-kinase is a key intermediate in many cellular responses induced by a vast array of divergent agonists, responses that result from the activation of downstream targets by proteins and lipids regulated by or generated from PI 3-kinase (5, 6). Several classes of PI 3-kinase, consisting of a catalytic subunit p110 (␣, ␤, and ␦) and regulatory subunit p85 (␣, ␤, and p55␥) or consisting of the catalytic subunit p110␥ and the regulatory subunit p101, have been described (for review see Ref. 7). Recent studies have demonstrated that the PI 3-kinase regulatory subunit p85␣ is critical for normal B cell development and proliferation (8, 9), whereas the catalytic subunits p110␤, p110␦, and p110␥ are involved in chemotactic responsiveness (10 -13).A large number of stimuli can activate a family of transcription factors termed NF-B/Rel (14, 15). These transcription factors are composed of homo/heterodimers of p50, RelA, RelB, and c-Rel (for review see Ref. 14). The activity of NF-B is controlled by NF-B inhibitors, IBs, a family of proteins, which bind to NF-B dimers, hiding their nuclear localization sequence resulting in cytoplasmic retention of NF-B (15, 16). NF-B also forms complexes with IB␣, which contains a nuclear export sequence, and the whole NF-B-IB␣ complex can be removed from the nucleus by exportin-mediated transport to the cytoplasm (17). Constitutive activation of NF-B has been detected in some lymphomas, melanomas, and breast cancers (18 -22). A direct link between activation of NF-B and PI 3-kinase by the association of the tyrosine phosphorylated IB␣ and the regulatory subunit of PI 3-kinase, p85␣, has recently been demonstrated (23). In addition, another mechanism of NF-B activation involving the catalytic (p110) subunit has been recently suggested (23). Interestingly, IL-1 stimulated the PI 3-kinase-dependent phosphorylation and transactivation of NF-B without nuclear translocation of NF-B, suggesting the alternative NF-B activation pathway not involving IB␣ (24).Urokinase-type plasminogen activator (uPA) is a serine protease that cleaves the extracellular matrix and stimulates the conversion of plasminogen to plasmin (25). Plasmin can directly mediate invasion by degrading matrix proteins such as collagen IV, fibronectin, and laminin or indirectly by activating matrix metalloproteinases 2, 3, and 9 and uPA (26 -29). Furthermore, uPA is also involved in cell adhesion and chemotaxis (25,30,31). It is well documented that uPA plays a crucial role in tumor metastasis, and overexpression of uPA in breast can-

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Emerging evidence indicates that brain microvascular endothelial cells play a critical role in brain development, maturation, and homeostasis. Acute or chronic insults, including oxidative stress, oxygen-glucose deprivation, trauma, infections, inflammatory cytokines, DNA damaging agents, beta-amyloid deposition, and endoplasmic reticulum stress induce brain endothelial cell dysfunction and damage, which can result in cell death. The homeostatic balance between endothelial cell survival and endothelial cell death is critical for brain development, remodeling, and repair. On the other hand, dysregulation of brain endothelial cell death exacerbates, or even initiates, several inflammatory, ischemic, and degenerative disorders of the central nervous system. In here, the morphological, biochemical, and functional characteristics of the brain endothelium and its contribution to brain homeostasis will be reviewed. Recent insights into modalities and regulatory pathways involved in brain endothelial cell death will be described. The effects of regulated and dysregulated endothelial cell death leading to angiogenesis will be outlined. The relevance of brain endothelial cell dysfunction and death to disease processes will be discussed with special reference to recent findings that could help translate current knowledge on brain endothelial cell apoptosis into new therapeutic strategies for the treatment of certain neurological disorders.