Molecular regulation of p73, a p53 family member, remains unclear. Here we report that p73 expression is significantly regulated by cell densities. In particular, we found that p73α and p73β are differentially regulated. While p73β protein levels were inversely correlated with cell densities, p73α protein levels behaved oppositely. We further showed that density-dependent changes of p73α follow the same patterns as E2F-1 and TAp73 mRNA levels, suggesting transcriptional regulation. Our data also suggest that high levels of p73β at lower densities may be due to increased protein stability. However, AIP-4/Itch appeared not to be involved in downregulation of p73β at high densities. Moreover, we also found that subcellular location of p73 isoforms changes with the culture density increases. While high level of p73β at low density was mainly presented in the nucleus, low levels of this protein at high densities were mainly in the cytosol. Taken together, these findings reveal a novel mechanism that differentially regulates p73 isoforms and underscores the role of cell-cell interaction in p73 regulation, which may advance our understanding of p73 expression and function in human cancers.

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