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Identification of a Transactivation Activity in the COOH-Terminal Region of p73 Which Is Impaired in the Naturally Occurring Mutants Found inHuman Neuroblastomas¹

Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717 [N. T., T. O., S. I., A. N.]; Department of Pathology, Sapporo Medical College, Sapporo 060-8556 [S. I.]; and First Department of Surgery, Hokkaido University School of Medicine, Sapporo 060-8638 [N. T., S. T.], Japan

p73 is a recently cloned tumor suppressor gene that is highly homologous to p53, and the products of both possess similar functions in inhibiting cell growth and inducing apoptosis. Interestingly, the COOH-terminal region of p53 displays no significant homology with that of p73. Moreover, p73 has an additional segment at its COOH terminus. Recently, we have found two mutations of p73 with amino acid substitution (P405R and P425L) in primary neuroblastomas. Because the region (amino acid residues 382–491) contains a glutamine- and proline-rich domain, we hypothesized that it has a transactivation function, and the mutations found in tumors result in loss of function. To test it, we used the yeast GAL4 DNA-binding fusion system. Yeast transformants expressing a GAL4-p73(1–112) or a GAL4-p73(380–513) fusion protein were grown in SD medium lacking histidine and tryptophan and exhibited a significant induction of ß-galactosidase activity. Transient transfection experiments revealed that both of fusion proteins could induce the chloramphenicol acetyltransferase activity in mammalian cells, indicating that the COOH-terminal as well as NH₂-terminal regions of p73 had significantly high levels of transactivation activity. Furthermore, the former activity was severely impaired in two naturally occurring mutant forms found in neuroblastomas. These suggest that, unlike p53, p73 has two domains with transactivation function, one in the NH₂-terminal region and the other in the COOH-terminal region. Loss of function mutation in the latter might be involved in tumorigenesis and/or tumor progression.

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