Effect of Mutant p53 Stability on Tumorigenesis and Drug Design|
Effect of Mutant p53 Stability on Tumorigenesis and Drug Design
In the May 15th issue of G&D, Dr. Guillermina Lozano (MD Anderson Cancer Center) and colleagues reveal how the stabilization of a mutated form of p53 affects oncogenesis, and lends startling new insight into the potential pitfalls of using Mdm2 inhibitors for cancer therapy.
"Our data are both exciting and sobering: we must classify tumors with respect to p53 mutation status prior to treatment,” emphasizes Dr. Lozano.
One function of the p53 tumor suppressor is to arrest the cell cycle in response to DNA damage. For years it has been the focus of intense cancer research, as mutations in p53 prevent cell cycle arrest and lead to unregulated cell growth. p53 is one of the most commonly mutated genes in human cancers.
Dr. Lozano’s research team now demonstrates how a particular mutated form of p53 – which is prevalent in human cancers – can become stable in some cells, where it facilitates cancer formation and metastasis. The scientists found that mutant p53 is inherently unstable in normal tissues, but can become stable in some cells.
The researchers discovered that the acquisition of additional mutations the p53-antaogonist, Mdm2, could effectively stabilize mutant p53. Transgenic mice engineered to harbor such mutations displayed enhanced tumor formation and metastasis, compared with littermates lacking only p53.
Targeted drug therapies aimed at activating p53 tumor suppressor activity via the disruption of the normal Mdm2/wild-type-p53 interaction will also disrupt the Mdm2/mutant-p53 interaction. Thus, these Mdm2 inhibitors will succeed in stabilizing mutant p53, and fail in preventing tumor metastasis.
Fat Chance: Brown vs. white fat cell specification
In the May 15th issue of G&D, Dr. Bruce Spiegelman (Dana Farber Cancer Institute) and colleagues elucidate the molecular pathway that induces cells to become energy-burning brown fat cells as opposed to energy-storing white fat cells.
Since brown adipose tissue (BAT) and white adipose tissue (WAT) have essentially antagonistic roles in energy homeostasis (WAT stores calories; BAT burns them), insight into the genetics of adipocyte specification is particularly interesting to those contemplating the conversion of white-to-brown fat cells as a therapeutic treatment for obesity and obesity-related disorders.
Dr. Spiegelman and colleagues previously identified the protein PRDM16 as a dominant regulator of brown fat cell determination. PRDM is selectively expressed in BAT, where it activates brown fat-specific gene expression and represses white fat-specific gene expression. The scientists have now answered the complicated question: How?
Dr. Spiegelman and colleagues discovered that PRDM16 is able to switch between an association with the co-repressor proteins, CtBP-1 and -2, to inhibit WAT genes, and the co-activator protein PGC-1alpha, to induce BAT gene expression. Thus, PRDM16 can differentially regulate fat cell gene expression programs to favor the formation of BAT.
Dr. Spiegelman feels that "As we learn more about the molecular mechanisms by which PRDM16 acts, we hope to be able to use this pathway to modulate metabolism in living organisms to counteract obesity and diabetes".
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