HIGHLIGHTS

HIGHLIGHTS ADVISORS JOAN S. BRUGGE HARVARD MEDICAL SCHOOL, BOSTON, MA, USA PASCALE COSSART The mafia INSTITUT PASTEUR, PARIS, FRANCE GIDEON DREYFUSS At the heart of a report in Nature lies a UNIVERSITY OF PENNSYLVANIA, tale of drugs and violent death. The PHILADELPHIA, PA, USA leading role in this story goes to p53, PAMELA GANNON which orders the apoptotic execution CELL AND MOLECULAR of cells in response to DNA-damaging BIOLOGY ONLINE agents such as doxorubicin. But as JEAN GRUENBERG Elsa Flores, Tyler Jacks and co-workers UNIVERSITY OF GENEVA, now show, this is a family affair — for SWITZERLAND p53 needs its close relatives p63 and ULRICH HARTL p73 to carry out the task. MAX-PLANCK-INSTITUTE, The structural and functional sim- MARTINSRIED, GERMANY ilarities between p53 and its relatives NOBUTAKA HIROKAWA led Jacks and colleagues to ask UNIVERSITY OF TOKYO, JAPAN whether p63 and p73 are involved in STEPHEN P. JACKSON the p53-dependent response to DNA- Courtesy of the Kobal Collection WELLCOME/CRC INSTITUTE, damaging agents. They studied this CAMBRIDGE, UK using mouse embryo fibroblasts Although other mechanisms of wild-type MEFs. However, in cells VICKI LUNDBLAD (MEFs) that had been sensitized to p53-dependent apoptosis have been that lacked p63 and p73, p53 could no BAYLOR COLLEGE OF undergo apoptosis by expression of proposed, there is a general consen- longer associate with the bax or PERP MEDICINE, HOUSTON, TX, USA the E1A and were deficient sus that p53 acts in this process by promoters in response to DNA dam- WALTER NEUPERT in various p53 family members. the initiation of downstream target age. Moreover, in p53-deficient MEFs, UNIVERSITY OF MUNICH, As expected, after treatment with genes. So, Jacks and colleagues stud- p63 was found specifically at the bax GERMANY doxorubicin, the p53–/– MEFs were ied the induction of p53 target and PERP promoters. TONY PAWSON resistant to apoptotic death. The genes in MEFs that lacked the vari- These results indicate a model in SAMUEL LUNENFELD RESEARCH p63–/– and p73–/– cells showed only a ous p53 family members. The which p63 and p73 regulate the ability INSTITUTE, TORONTO, CANADA partial resistance to apoptosis, but induction of some targets, such as of p53 to bind at certain promoters NORBERT PERRIMON MEFs that lacked both of these genes p21 and , was no different in after its induction in response to DNA HARVARD MEDICAL SCHOOL, were as resistant to apoptosis as were wild-type cells than in cells that damage. And, as the authors specu- BOSTON, MA, USA the p53–/– cells. Moreover, cells that lacked p63, p73 or p63/p73. But late, they might “portend a greater THOMAS D. POLLARD lacked p53/p63 or p53/p73 were other genes — bax and PERP,for role for these proteins in tumour sup- THE SALK INSTITUTE, more resistant than MEFs that were example — were not expressed in pression and chemosensitivity”. LA JOLLA, CA, USA deficient in p53 alone, and this indi- MEFs that lacked p63 and p73. Alison Mitchell JOHN C. REED cated that p63 and p73 might act with Notably, Bax and PERP are linked References and links THE BURNHAM INSTITUTE, p53 — or in a parallel pathway — to to apoptotic responses. ORIGINAL RESEARCH PAPER Flores, E. R. et LA JOLLA, CA, USA induce apoptosis after DNA damage. The authors had shown that both al. p63 and p73 are required for p53-dependent KAREN VOUSDEN p53 and p63 are enriched in the nuclei apoptosis in response to DNA damage. Nature The authors confirmed these results 416, 560–564 (2002) NATIONAL CANCER INSTITUTE, in an in vivo system — the developing of MEFs after DNA damage, so they FURTHER READING Yang, A. & McKeon, F. p63 FREDERICK, MD, USA nervous system of day-13.5 mouse tested whether these proteins can bind and p73: p53 mimics, menaces and more. Nature JOHN WALKER embryos, in which p53 has been the promoters of p53 target genes. Rev. Mol. Cell Biol. 1, 199–207 (2000) WEB SITE MRC DUNN HUMAN NUTRITION shown to be important for γ-irradia- Both proteins associated with the p21, UNIT, CAMBRIDGE, UK Tyler Jacks’ laboratory: http://web.mit.edu/biol- tion-induced apoptosis. mdm2, bax and PERP promoters in ogy/www/facultyareas/facresearch/jacks.shtml

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