Signaling Pathways Controlling c-Myc Degradation Shown to Affect Oncogenic Transformation of Human Cells

In the April issue of Nature Cell Biology, Dr. Elizabeth Yeh and colleagues describe a sequence of molecular events that regulates the stability of the c-Myc protein, a transcription factor essential for normal cell proliferation that modulates the expression of genes involved in cell-cycle control, differentiation, and apoptosis. c-Myc is overexpressed in many human cancers, and when too much of the c-Myc protein accumulates by failing to degrade, it contributes to oncogenesis.

Scientists have known that activation of the Ras signaling pathway stabilizes the normally short-lived c-Myc protein and that deactivation of Ras signaling allows degradation of the protein via the ubiquitin-proteasome pathway. Yeh and colleagues have elucidated the mechanisms that control this sequence of events - specifically, the sequential phosphorylation of two highly conserved amino acid residues, serine 62 (Ser 62) and threonine 58 (Thr 58).

During Ras activation, the c-Myc protein is phosphorylated at Ser 62, which stabilizes it, allowing its effects on the cell to become amplified. To ensure that the subsequent increase in the amount of protein is temporary, Ser 62 phosphorylation triggers a cascade of molecular interactions that culminate with the phosphorylation of Thr 58. This second phosphorylation event tags the protein for degradation. The authors conclude, therefore, that "the role of the inter-related phosphorylation and dephosphorylation events is to ensure that Ras-mediated amplification of c-Myc protein levels is indeed transient and self-limited.

"Several types of cancer - including Burkitt's lymphoma and all cancers caused by retroviruses - have been found to possess the form of the c-Myc protein that is mutated at Thr 58. As the authors observe, "at least one functional consequence of c-Myc stabilization in human cells is to sensitize the cells to transformation and tumorigenesis."

Halting of Antitobacco Campaign Increases Youth Smoking Susceptibility

The discontinuation of an aggressive advertising campaign aimed at reducing tobacco use in teens increased the number of adolescents susceptible to cigarette smoking, according to a new study from University of Miami and NCI researchers. Six months after a comprehensive Minnesota state antitobacco campaign ceased in July 2003 due to massive cutbacks in funding for antismoking programs, the number of adolescents who said they would smoke sometime in the next year increased from 43.3 percent to 52.9 percent.

In the analysis, published in the April 16 Morbidity and Mortality Weekly Report, researchers looked at results from surveys of more than 1,000 teens aged 12 to 17. The surveys, conducted during and after the three-year antitobacco campaign, were devised to gauge teens' awareness. The teens were specifically asked about their awareness of the campaign's Target Market branding and whether they would smoke in the next year.

Studies have shown that comprehensive state antitobacco programs, especially those with strong advertising (i.e., paid media) campaigns, have contributed to the substantial decline in adolescent smoking since 1997, the researchers noted. "These findings suggest that state cutbacks in anti-tobacco campaigns might increase the susceptibility of youths to smoking, which is a key predictor of adolescent tobacco use," they wrote. "Because tobacco use remains the leading preventable cause of death in the United States, efforts to prevent smoking initiation among youths can have a profound impact on public health."

Trial Testing Rituximab for Indolent NHL Reaches Endpoint Two Years Early

A phase III clinical trial evaluating the anti-CD20 monoclonal antibody rituximab (Rituxan) in patients with relapsed indolent non-Hodgkins lymphoma (NHL) has met its primary endpoints of response rate and progression-free survival two years earlier than expected, the drug's manufacturer, Roche, has announced.

In the trial, which involved sites in 18 countries, 321 relapsed indolent NHL patients were randomly assigned to receive rituximab plus chemotherapy or chemotherapy alone as initial treatment. Responding patients were then randomly assigned to receive either rituximab for two years as maintenance therapy or no further treatment. An interim analysis demonstrated rituximab's superior efficacy in both parts of the trial. With chemotherapy alone, the median point for time to progression of the disease was 15 months, while chemotherapy plus rituximab extended this to 27 months.