TAp63 plays compensatory roles in p53-deficient cancer cells under genotoxic stress

p53, p63, and p73 belong to the p53 family of proteins, which mediate development, differentiation, and various other cellular responses. p53 is involved in many anti-cancer mechanisms, such as cell cycle regulation, apoptosis, and the maintenance of genomic integrity. The p63 gene is controlled by two promoters that direct the expression of two isoforms, one with and one without transactivating properties, known as TAp63 and ΔNp63. In this study, p53-deficient cells (Hep3B and PC-3) and p53-expressing cells (A549 and HepG2) were treated with doxorubicin to examine the possible roles of TAp63 in these cells under genotoxic stress; TAp63 expression was induced in p53-deficient cell lines, but not in p53-expressing cell lines. The ectopic expression of p53 in p53-deficient cells (Hep3B) reduced TAp63 promoter activity, and knockdown of TAp63 attenuated doxorubicin-induced cell growth arrest by promoting cell cycle progression, leading to an increase in the percentage of G(2)/M cells. Moreover, knockdown of TAp63 increased cell sensitivity to doxorubicin-induced genomic damage. Our results suggest that TAp63 may play a compensatory role in cell cycle regulation and DNA damage repair in p53-deficient cancer cells.     

4-Hydroxynonenal modulation of p53 family gene expression in the SK-N-BE neuroblastoma cell line

4-Hydroxynonenal (HNE), a product of lipid peroxidation, inhibits proliferation of several tumor cells. The p53 tumor suppressor protein plays a critical role in cell cycle control, by inducing p21 expression, and in apoptosis, by inducing bax expression. Recently, two other proteins with many p53-like properties, TAp73 (p73) and TAp63 (p63), have been discovered. SK-N-BE human neuroblastoma cells express the three p53 family proteins and can be used for the study of their induction. We investigated HNE action in the control of proliferation, differentiation, and apoptosis in SK-N-BE cells and the HNE effect on the expression of p53, p63, p73, p21, bax, and G1 cyclins. Retinoic acid (RA) was used as a positive control. HNE inhibited cell proliferation without inducing differentiation; it decreased S-phase cells and increased the number of apoptotic cells. RA reduced the proportion of S-phase cells and did not induce apoptosis. HNE increased p53, p73, p63, p21, and bax expression at different time points. HNE reduced cyclin D2 expression and the phosphorylation of pRb protein. Our results demonstrated that HNE inhibits SK-N-BE cell proliferation by increasing the expression of p53 family proteins and p53 target proteins which modulate cell cycle progression and apoptosis.     

TAp73/Delta Np73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma

We investigated the mechanisms by which TAp73 beta and dominant-negative p73 (Delta Np73) regulate apoptosis. TAp73 beta transactivated the CD95 gene via the p53-binding site in the first intron. In addition, TAp73 beta induced expression of proapoptotic Bcl-2 family members and led to apoptosis via the mitochondrial pathway. Endogenous TAp73 was upregulated in response to DNA damage by chemotherapeutic drugs. On the contrary, DeltaNp73 conferred resistance to chemotherapy. Inhibition of CD95 gene transactivation was one mechanism by which DeltaNp73 functionally inactivated the tumor suppressor action of p53 and TAp73 beta. Concomitantly, DeltaNp73 inhibited apoptosis emanating from mitochondria. Thus, DeltaNp73 expression in tumors selects against both the death receptor and the mitochondrial apoptosis activity of TAp73 beta. The importance of these data is evidenced by our finding that upregulation of DeltaNp73 in hepatocellular carcinoma patients correlates with reduced survival. Our data indicate that Delta Np73 is an important gene in hepatocarcinogenesis and a relevant prognostic factor.     

The p53 family: same response, different signals?

TP53, the gene that encodes p53, is a well-defined tumor suppressor gene that is frequently mutated in human cancers. Recently, two proteins homologous to p53, termed p73 and p63, were identified. Current data indicate that both p73 and p63, like p53, can induce cell-cycle arrest and apoptosis, suggesting that they might also be tumor suppressors. However, the physiological signals that can regulate p53, for example, DNA damage, have no effect on p73, as tested in several cell lines. Furthermore, the signaling pathways by which p73 (and possibly p63) induces cell-cycle arrest and apoptosis appear to be similar to those of p53, but also have important differences. Thus, the p53 family proteins are closely related but might have distinct physiological functions.