C-Myc is one such oncogene, and in fact it appears to be unusually powerful in terms of its ability to induce the cellular changes associated with cancer.

Two papers in the current issue of Molecular Cell provide new evidence about some of the mechanisms by which it may do this, and links them to oxidative stress.

Researchers from the Salk Institute in California examined the relationship between c-Myc and DNA damage and propose a novel mechanism for oncogene-induced genetic instability.

They demonstrated that short-term activation of c-Myc induced oxidative stress, i.e., excessive production of reactive oxygen species (ROS), normal byproducts of cellular metabolism, can cause problems if present in excessive amounts.

The activation of c-Myc caused DNA damage, which, importantly, could be reduced by preventing ROS build-up.

The scientists reported that c-Myc inhibited the p53 pathway that would normally stop cell proliferation upon DNA damage. Therefore, c-Myc increased DNA damage and simultaneously compromised the damage-sensing mechanism, thereby increasing the probability that damaged DNA would be copied and inherited by daughter cells.

According to the authors, “While most cells with DNA damage would be expected to die, rare survivors with additional mutations that improve survival, such as those that completely disable the p53 pathway, would be expected to arise.”

The authors propose that their results provide a potential mechanism for how oncogene activation induces genetic abnormalities and drives cellular proliferation.

In the second paper, a group of scientists from Japan made cells that contained activated c-Myc or activated E2F1 (another factor that drives cell proliferation and is also often observed to be mutated in tumors).

They found that c-Myc enhanced E2F1 activation, resulting in an accumulation of a byproduct of cell metabolism called reactive oxygen species (ROS) and a subsequent enhancement of apoptosis.

Most normal cells can generate enzymes to remove excess ROS, a process that is stimulated by a molecule called NF-kB, which is a known inhibitor of apoptosis.

The researchers found that E2F1 directly inhibits NF-kB. They concluded that c-Myc-induced apoptosis is regulated, at least in part, by E2F1 inhibition of the cell survival factor NF-kB.

While the mechanism for regulation of apoptosis that is proposed in this paper is just one in a very complicated system, the authors suggest that the ability of E2F1 to inhibit NF-kB and make cells more susceptible to apoptosis make it a candidate tumor suppressor.

Understanding the mechanisms that regulate cell growth and survival is vital for identifying potential targets for future cancer therapeutics. Together, these papers provide an illustration of how a single oncogene, in this case c-Myc, can affect a number of different cellular pathways to promote cancer progression.

They also show one way in which different cancer mutations can co-operate to generate a stronger effect than either would alone.

Finally, they link c-Myc activity in tumorigenesis to oxidative stress, providing further support for the view that dietary and environmental antioxidant activity could be beneficial in helping to stave off cancer.

(Reference: Volume 9 Number 5 May 2002, Molecular Cell.)


[Contact: Dr. Geoffrey M. Wahl, Dr. Itaru Matsumura ]

24-May-2002