Human Cells Producing Proteins

In the January 15 issue of Nature, NCI scientists reported the discovery of a new mechanism in human cells for producing proteins. This involves cutting a protein into smaller pieces, which are then rejoined in a different order. The finding suggests that human cells may be able to produce a far greater range of proteins than was previously thought. Two of the authors, Dr. Ken-ichi Hanada and Dr. James C. Yang, are from NCI's Surgery Branch.

The researchers were studying fragments of a protein known as fibroblast growth factor-5 (FGF-5), which was overproduced in the tumor cells of a kidney cancer patient. In the process of trying to determine which portion of the FGF-5 protein is recognized by the patient's killer T cells, they discovered that the T cells recognize two stretches of the protein that are not next to each other. This led them to conclude that after the FGF-5 protein is produced in the cell, it is cut into pieces, which are then stitched together in a different order. The enzymes for cleaving the protein or stitching the pieces back together are not known. Similar protein processing has been reported in single-celled organisms and some plants.

Novel Mechanism Allows HTLV-1 to Mask Its Presence

The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) has evolved to develop a novel mechanism for inhibiting its expression, a function that may mask its presence in infected cells, researchers from the NCI report in the January 2004 issue of Nature Medicine. The finding may explain why HTLV-1 can persist despite the body's robust immune response to it.

Dr. Genoveffa Franchini and colleagues from the Animal Models and Retroviral Vaccines Section, Center for Cancer Research, found that a nuclear-resident protein of HTLV-1, p30II, is able to reduce the levels of the Tax and Rex proteins, which play critical roles in virus expression.

"This protein is able to modulate viral expression and may help the virus to remain concealed and avoid elimination by the host immune system," Dr. Franchini said. The researchers studied p30II's effect at the post-transcriptional level as well as during transcription. The finding was that the real action was occurring after transcription of viral messenger RNAs, with p30II specifically targeting the Tax and Rex mRNA, but strictly in the cell nucleus.

The novelty of this finding, Dr. Franchini explained, is that retroviruses are thought to become latent through cellular mechanisms, "leaving it to the cell to decide its own fate." The protein p30II "puts the virus more in charge of what it wants to do."

A high viral replication correlates with a higher probability of developing leukemia. Therapies that can block the interaction of p30II with the viral RNA, Dr. Franchini suggested, will unmask the virus, "meaning the virus will be expressed and more overt to the immune system, and that might facilitate its elimination."

Smoking Reduction Fails to Proportionally Decrease Carcinogen Exposure

The good news from a study in the January 21 issue of the Journal of the National Cancer Institute (JNCI) is that exposure to the potent tobacco carcinogen NNK can be significantly reduced in smokers who substantially reduce their daily cigarette intake. The bad news, according to the University of Minnesota Cancer Center researchers who conducted the NCI-funded study, is that the reduction is not proportional to the reduction in cigarettes smoked. In a related JNCI commentary, an international team of epidemiologists reported that a review of the evidence accumulated over the past 16 years reveals that there is a causal relationship between tobacco use and cancers not previously believed to be associated with smoking, including myeloid leukemia and cancers of the stomach and liver.

"Together, these articles serve as a poignant reminder that tobacco's role as a cancer initiator and promoter…remains one of the greatest global public health challenges," wrote Drs. Scott Leischow and Mirjana Djordjevic, of the NCI Tobacco Control Research Branch, in an accompanying editorial. "The most dramatic health benefits in the next half century will occur if we can significantly increase the number of smokers who quit."