Highlights of This Issue

Abstract

The uPA-uPAR system is upregulated in a large proportion of human cancers. Gorantla and colleagues have shown that suppression of this system retards angiogenesis, invasion, and tumor development in pancreatic cancer cells. Suppression of this system was accompanied by the upregulation of RANTES, a known monocyte recruiter. Further, the authors provide evidence for the first time of the possible regulatory role of uPA from its interaction with Lhx-2 in the nucleus, thus emphasizing the importance of targeting the uPA-uPAR system in invasive cancers.p53 mediates multiple checkpoint pathways in response to cellular stress. The relative contribution each of the diverse p53-dependent functions plays in tumor suppression is poorly defined, especially in the context of epithelium-derived tumors. Lu and colleagues show that reduced apoptosis caused by Bax deficiency significantly alleviates the selective pressure for p53 inactivation in a murine carcinoma model. Apoptosis is therefore the primary target of selective pressure in this tumor setting, whereas the loss of other pleiotropic p53 functions further increases tumor malignancy. Elucidating the hierarchy of p53-mediated pathways enhances our understanding the mechanisms underlying tumor evolution.E2F1, a pivotal transcription factor that can induce both proliferation and cell death is a critical downstream target of the tumor suppressor retinoblastoma (RB). The RB pathway is often inactivated in human tumors resulting in deregulated E2F activity. Whereas the role of E2F1 in transcriptional regulation of proteinencoding genes is well characterized, its function as a regulator of microRNA is less well studied. Ofir and coworkers show that E2F1 transcriptionally regulates the expression of the cancer-related microRNAs miR-15 and miR-16. This regulation serves to fine-tune E2F1 activity by attenuating both E2F1-induced upregulation of cyclin E and E2F1-mediated cell cycle progression.Regulation of ribonucleotide reductase (RNR) activity and thus dNTP levels is a key control point after DNA damage. Dyavaiah and colleagues have shown that the S. cerevisiae RNR large subunit protein, ribonucleotide reductase 1 (Rnr1), is specifically packaged into an autophagosome, targeted to the vacuole, and degraded in response to inhibition of target of rapamycin (TOR). They have also shown that defects in autophagy promote increased Rnr1 protein levels and a DNA damage phenotype. Their findings suggest that the increased genome instability and carcinogenesis observed in autophagydeficient human cells could be due to misregulation of DNA damage response proteins.