STKE: Targeting Downstream Repercussions

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Science  24 Feb 2006:
Vol. 311, Issue 5764, pp. 1075c
DOI: 10.1126/science.311.5764.1075c

The tumor suppressor p53, which enforces cell-cycle arrest or cell death, is mutated in roughly half of malignant tumors. Nutlins are imidazoline compounds that disrupt the interaction between p53 and the E3 ubiquitin ligase MDM2 that targets p53 for degradation. Tovar et al. show that in 10 cell lines (representing a range of solid tumors) that express wild-type p53, adding nutlin-3a (and hence freeing p53) resulted in cell-cycle arrest although the extent of apoptosis varied. The osteosarcoma cell line SJSA-1, which has a highly amplified mdm2 gene, was the most sensitive to nutlin-3a-induced apoptosis. To verify that mdm2 amplification was responsible, two other osteosarcoma cell lines—MHM, which has a moderately amplified mdm2, and U2OS, which has a single copy of mdm2—were also analyzed. All three exhibited cell-cycle arrest when exposed to nutlin-3a; however, the induction of apoptosis varied with mdm2 copy number. Microarray analysis showed that proapoptotic genes, such as puma, noxa, and bax, were more strongly stimulated in cells with amplified mdm2 in response to nutlin-3a. Finally, nutlin-3a caused tumor regression in nude mice with MHM and SJSA-1 tumors and halted the growth of tumors that had normal MDM2 and p53. These results suggest that (i) nutlins may be effective clinically, especially for tumors with mdm2 amplification and (ii) cancer cells with normal p53 may have defects in the p53 apoptotic pathway. — NRG

Proc. Natl. Acad. Sci. U.S.A. 103, 1888 (2006).

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