Biomedical subjects

Kai Wei Lin

Publications and source records attributed to Kai Wei Lin.

2 recordsLinked to original sources

PubMed2004

c-Jun regulates the stability and activity of the p53 homologue, p73.

Chemotherapeutic drugs and stress signals activate p73, the structural and functional homologue of p53, both by transcriptional activation and post-translational modifications. However, cisplatin, a DNA damage-inducing chemotherapeutic agent, is thought to regulate p73 only by affecting its stability through mechanisms involving the MLH-1/c-Abl signaling cascade. Here we show that c-Jun, a component of the AP-1 family of transcription factors, contributes to p73 induction by cisplatin. c-jun(-/-) cells are defective in p73 induction, and ectopic c-Jun expression augments p73 levels. c-Jun-mediated accumulation of p73 requires the transactivation activity of c-Jun and occurs in a c-Abl- and Mdm2-independent manner. c-Jun expression increases p73 half-life by preventing it from proteasome-mediated degradation, resulting in the potentiation of p73-mediated transcriptional activity. Moreover, mouse fibroblasts lacking c-Jun are resistant to cisplatin-induced apoptosis, and reintroduction of c-Jun restores p73 activation and sensitivity to cisplatin. Furthermore, p73-mediated apoptosis is abrogated in c-jun(-/-) cells. Together, these findings demonstrate a possible role for c-Jun in regulating p73 function and highlight the importance of the cooperativity between transcription factors in potentiating apoptosis.

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PubMedDate not supplied

Multiple stress signals induce p73beta accumulation.

Although p73 is a structural and functional homologue of the tumor-suppressor gene p53, it is not mutated in many human cancers as p53. Besides, p73 was shown to be activated by only a subset of signals that activate p53, such as gamma-irradiation and cisplatin, but not by other common genotoxic stress-inducing agents such as ultraviolet (UV) irradiation, although many of these signals are also capable of inducing p53-independent cell death. Using a p73-specific antibody, we confirmed that c-Abl is required for cisplatin-induced p73 upregulation, and further demonstrate that the p73 protein is upregulated by UV irradiation and other stress stimuli including sorbitol, hydrogen peroxide, nocodazol, and taxol. These stress signals upregulate both p73 mRNA and increases the stability of p73, indicating that p73 is regulated transcriptionally and posttranslationally. Cells stably expressing the dominant-negative p73 inhibitor protein (p73DD) and p73(-/-) fibroblasts are more resistant than control cells to apoptosis induced by these stress signals, suggesting that p73 contributes to apoptosis induction. Together, the data demonstrate that several stress signals can signal to p73 in vivo, which raises the possibility of eradicating cancers with an unmutated p73 gene by activating them with stress-inducing agents or their mimetics.

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