In good times and bad: p73 in cancer.

It is widely accepted in cancer biology that p53 has a tumor suppressive activity, which is lost during tumorigenesis most frequently by mutations in the p53 gene. The discovery of p73 as the first homologue of p53 raised immediate expectations about p53-like tumor suppressor activities. Although tumors show changes in the expression level of p73 and differences in the expression pattern of p73 isoforms, mutations are not commonly observed making it difficult to infer p73's role in tumorigenesis. An experimental model of human cell transformation closely mimics the expression changes observed in cancer patients and provides novel insights into the regulation and function of p73 in the various steps on the road to malignant transformation. p53-like isoforms of p73 (TAp73) are upregulated early during the transformation process in response to RB pathway alterations and block progression to the fully transformed state. Antagonists of TAp73 such as the dominant-negative p73 protein DeltaNp73 overcome this block and pave the way to full transformation. Here we review these findings in the context of patient data and recent advances on molecular aspects of p73 function and discuss the implications for p73 as a target for cancer therapy.

p73 poses a barrier to malignant transformation by limiting anchorage-independent growth.

p53 is known to prevent tumour formation by restricting the proliferation of damaged or oncogene-expressing cells. In contrast, how the p53 family member p73 suppresses tumour formation remains elusive. Using a step-wise transformation protocol for human cells, we show that, in premalignant stages, expression of the transactivation-competent p73 isoform TAp73 is triggered in response to pRB pathway alterations. TAp73 expression at this stage of transformation results in increased sensitivity to chemotherapeutic drugs and oxidative stress and inhibits proliferation and survival at high cell density. Importantly, TAp73 triggers a transcriptional programme to prevent anchorage-independent growth, which is considered a crucial hallmark of fully transformed cells. An essential suppressor of anchorage-independent growth is KCNK1, which is directly transactivated by TAp73 and commonly downregulated in glioma, melanoma and ovarian cancer. Oncogenic Ras switches p73 expression from TAp73 to the oncogenic deltaNp73 isoform in a phosphatidyl-inositol 3-kinase-dependent manner. Our results implicate TAp73 as a barrier to anchorage-independent growth and indicate that downregulation of TAp73 is a key transforming activity of oncogenic Ras mutants.

p53 family members in myogenic differentiation and rhabdomyosarcoma development.

The p53 family comprises the tumor suppressor p53 and the structural homologs p63 and p73. How the three family members cooperate in tumor suppression remains unclear. Here, we report different but complementary functions of the individual members for regulating retinoblastoma protein (RB) function during myogenic differentiation. Whereas p53 transactivates the retinoblastoma gene, p63 and p73 induce the cyclin-dependent kinase inhibitor p57 to maintain RB in an active, hypophosphorylated state. DeltaNp73 inhibits these functions of the p53 family in differentiation control, prevents myogenic differentiation, and enables cooperating oncogenes to transform myoblasts to tumorigenicity. DeltaNp73 is frequently overexpressed in rhabdomyosarcoma and essential for tumor progression in vivo. These findings establish differentiation control as a key tumor suppressor activity of the p53 family.