Identification of a transactivation activity in the COOH-terminal region of p73 which is impaired in the naturally occurring mutants found in human neuroblastomas.
نویسندگان
چکیده
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-p73alpha(380-513) fusion protein were grown in SD medium lacking histidine and tryptophan and exhibited a significant induction of beta-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.
منابع مشابه
Naturally Occurring Mutants Found inHuman Neuroblastomas COOH-Terminal Region of p73 Which Is Impaired in the Identification of a Transactivation Activity in the
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...
متن کاملDeletion of the COOH-terminal region of p73alpha enhances both its transactivation function and DNA-binding activity but inhibits induction of apoptosis in mammalian cells.
The candidate tumor suppressor p73 has a high sequence homology with p53 within the NH2-terminal transactivation domain, the sequence-specific DNA-binding region, and the oligomerization domain. However, p73alpha, which is most abundantly expressed in many tissues and cells among the alternatively spliced forms of p73, has an additional long COOH-terminal tail that might distinguish the functio...
متن کاملInhibits Induction of Apoptosis in Mammalian Cells Its Transactivation Function and DNA-binding Activity
The candidate tumor suppressor p73 has a high sequence homology with p53 within the NH2-terminal transactivation domain, the sequencespecific DNA-binding region, and the oligomerization domain. However, p73a, which is most abundantly expressed in many tissues and cells among the alternatively spliced forms of p73, has an additional long COOH-terminal tail that might distinguish the function of ...
متن کاملPossible Oncogenic Potential of Np73: A Newly Identified Isoform of Human p73
p73, a recently identified gene highly homologous to p53, can transactivate p53 target genes and induce apoptosis. Here we report the identification of an NH2-terminal truncated isoform of human p73, Np73, which is capable of suppressing p53and p73-dependent transactivation. We speculate that this suppression is achieved by competing for the DNA binding site in the case of p53 and by direct ass...
متن کاملIn silico mutational analysis and identification of stability centers in human interleukin-4
Interleukin-4 (IL-4) is a multifunctional cytokine that plays a critical role in apoptosis, differentiation and proliferation. The intensity of IL4 response depends upon binding to its receptor, IL-4R. The therapeutic efficiency of interleukins can be increased by generating structural mutants having greater stability. In the present work, attempts were made to increase the stability of human I...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Cancer research
دوره 59 12 شماره
صفحات -
تاریخ انتشار 1999