Stabilization of p73 by nuclear IkappaB kinase-alpha mediates cisplatin-induced apoptosis.

In response to DNA damage, p53 and its homolog p73 have a function antagonistic to NF-kappaB in deciding cell fate. Here, we show for the first time that p73, but not p53, is stabilized by physical interaction with nuclear IkappaB kinase (IKK)-alpha to enhance cisplatin (CDDP)-induced apoptosis. CDDP caused a significant increase in the amounts of nuclear IKK-alpha and p73alpha in human osteosarcoma-derived U2OS cells.

p73 and MDM2 confer the resistance of epidermoid carcinoma to cisplatin by blocking p53.

p73 responds to DNA damage and exerts its pro-apoptotic function. However, p73 might contribute to the development of drug-resistance in certain tumor cells. In this study, we found that p73 and MDM2 correlate with cisplatin-resistant phenotype of human epidermoid carcinoma-derived cells.

UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination.

p73 protein level is kept extremely low in mammalian cultured cells and its stability may be regulated by not only the ubiquitin/proteasome-dependent proteolysis but also through other unidentified mechanisms. Here, we found for the first time that p73 is physically as well as functionally associated with the U-box-type E3/E4 ubiquitin ligase UFD2a. The immunoprecipitation experiments demonstrated that this interaction is mediated by the COOH-terminal region of p73alpha containing SAM domain.

Functional implication of p73 protein stability in neuronal cell survival and death.

p73, a newly identified member of p53 family, locates at human chromosome 1p36.2-3, a region which is frequently deleted in a wide variety of human tumors including neuroblastoma. p73 is induced to be accumulated in response to a subset of DNA damaging agents such as cisplatin, and thereby promoting G1/S cell cycle arrest and/or apoptosis.

Identification of protein kinase A catalytic subunit beta as a novel binding partner of p73 and regulation of p73 function.

Post-translational modifications play a crucial role in regulation of the protein stability and pro-apoptotic function of p53 as well as its close relative p73. Using a yeast two-hybrid screening based on the Sos recruitment system, we identified protein kinase A catalytic subunit beta (PKA-Cbeta) as a novel binding partner of p73. Co-immunoprecipitation and glutathione S-transferase pull-down assays revealed that p73alpha associated with PKA-Cbeta in mammalian cells and that their interaction was mediated by both the N- and C-terminal regions of p73alpha.

Polo-like kinase 1 (Plk1) inhibits p53 function by physical interaction and phosphorylation.

Polo-like kinase 1 (Plk1) has an important role in the regulation of M phase of the cell cycle. In addition to its cell cycle-regulatory function, Plk1 has a potential role in tumorigenesis. Here we found for the first time that Plk1 physically binds to the tumor suppressor p53 in mammalian cultured cells, and inhibits its transactivation activity as well as its pro-apoptotic function.

Physical interaction of p73 with c-Myc and MM1, a c-Myc-binding protein, and modulation of the p73 function.

p73 shares high sequence homology with the tumor suppressor p53. Like p53, ectopic overexpression of p73 induces cell cycle arrest and/or apoptosis, and these biological activities are linked to its sequence-specific transactivation function. The COOH-terminal region of p73 is unique and has a function to modulate DNA-binding ability and transactivation activity.