Editors' ChoiceTumorigenesis

Positive Repression

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Science Signaling  15 Jul 2008:
Vol. 1, Issue 28, pp. ec253
DOI: 10.1126/scisignal.128ec253

Although the transmembrane protein CD44 does not itself signal, its association with tumor cell growth and metastasis is probably due to its ability to costimulate growth factor receptor signaling. Noticing a correlation between the abundance of CD44 and that of mutant forms of the tumor suppressor protein p53 in various carcinomas, Godar et al. investigated the relationship between p53 and CD44 in human breast primary epithelial cells (BPECs). Immunofluorescent staining and Western blotting analyses revealed the mutually exclusive presence of p53 and CD44 in immortalized BPEC (BPEC-T) cells. The abundance of CD44 protein was higher in BPEC-T cells treated with p53-specific short hairpin RNA (shRNA) than in control cells, which, together with semiquantitative reverse transcription polymerase chain reaction assays, suggested the repression of CD44 expression by p53. Indeed, CD44 was more abundant in the mammary glands of p53–/– mice than in those of wild-type mice. Reporter assays and gel-shift analysis showed that p53 directly repressed CD44 expression, and this direct interaction was confirmed by chromatin immunoprecipitation assays. Stimulation of cell proliferation by epidermal growth factor was greater in cells that overexpressed CD44 than in wild-type cells, which was also true for cells in which p53 was knocked down with shRNA. Cells overexpressing CD44 were more resistant to drug-induced, p53-dependent apoptosis than were control cells. Although transformed (p53-inactivated) BPEC-T cells formed tumors when transferred to susceptible mice, those treated with CD44-specific shRNA formed fewer and smaller tumors. Together, these data suggest that the basal abundance of p53 in mammary epithelial cells is sufficient to repress CD44 expression and thus prevent growth and tumor initiation.

S. Godar, T. A. Ince, G. W. Bell, D. Feldser, J. L. Donaher, J. Bergh, A. Liu, K. Miu, R. S. Watnick, F. Reinhardt, S. S. McAllister, T. Jacks, R. A. Weinberg, Growth-inhibitory and tumor-suppressive functions of p53 depend on its repression of CD44 expression. Cell 134, 62-73 (2008). [PubMed]

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