Transcription-independent and -dependent p53-mediated apoptosis in response to genotoxic and non-genotoxic stress

Abstract

We previously reported that p53-mediated apoptosis is determined by severity of DNA damage, not by the level of p53, in doxorubicin-treated prostate cancer cells. In addition to doxorubicin, our results here indicated that camptothecin and bortezomib, which are a topoisomerase 1 poison and a 26 S proteasome inhibitor, respectively, could also induce apoptosis in a p53-dependent manner in prostate cancer. Then, we examined whether p53-mediated apoptosis induced by genotoxic and non-genotoxic stress occur in the same or a different way. By using dominant negative p53 to compete with wild-type p53 in transcription activity, we demonstrated that p53-mediated apoptosis in response to doxorubicin- or camptothecin-induced genotoxic stress is transcription-independent. In contrast, p53-mediated apoptosis from bortezomib-induced stress is transcription-dependent. Interestingly, we also found that doxorubicin-induced p21 expression is activated by p53 in transcription-dependent manner, while camptothecin-induced p21 expression is p53-independent. We then investigated the p53 ratio of nucleus to cytosol corresponding to low and high dose doxorubicin, camptothecin, or bortezomib treatment. The results suggested that p53 translocation from cytoplasm to nucleus actively drives cells toward apoptosis in either transcription-dependent or -independent manner for responding to non-genotoxic or genotoxic stress, respectively.

P73 C-terminus is dispensable for multiciliogenesis

“…The p53 family proteins, including p53, p63 and p73 [1][2][3][4][5][6], share a functional and molecular interconnection in the cascade of events triggered by the DNA damage response [7][8][9][10][11][12]: genotoxicity triggers activation of these transcriptional factors leading to activation of a shared transcriptional signature, including p21, Bax, PUMA and NOXA, which is responsible for the p53 family effects on cell cycle progression and apoptosis [11,[13][14][15][16][17]. However, while the best characterized family member, p53, plays major role in tumor suppression [18][19][20][21][22][23][24][25][26][27], the homologue p73, also exerts fundamental independent functions [3,[28][29][30].…”

Toxicity and Anti-Proliferative Properties of Anisomeles indica Ethanol Extract on Cervical Cancer HeLa Cells and Zebrafish Embryos

“…Previously, p21 has been reported as a key molecule, which plays an important role in regulation of the critical G1 to S phase transition of the cell cycle, senescence and apoptosis, and to be positively regulated by p16 [ 16 ]. Moreover, previous studies demonstrated that p21 could be up-regulated and resulted in cell cycle arrest at G1 phase in a p53-independent manner [ 17 , 18 , 36 ]. In addition, it had been also revealed that paclitaxel could induce the cell apoptosis with a p53-independent way [ 37 ].…”

“…On the other hand, the cell cycle is regulated by Cyclin-Dependent Kinases (CDKs), which are activated at specific points during progression of the cell cycle. Arresting the cell cycle at any phase of G1, S, and G2/M of the cell cycle inhibits cell division and may ultimately cause cell death [ 13 , 14 , 15 , 16 , 17 , 18 ].…”

Cancer predictive studies

“…p53, p63 and p73 define the p53 family of transcription factors. All three are transcribed as several distinct protein isoforms [ 37 – 40 ]. Two alternative promoters drive the expression of either a transcriptionally active p73 (TA isoforms) proteins [ 41 ], containing a full N-terminal transactivation domain (TAD), or a N-terminally truncated (ΔN isoforms) proteins [ 42 ], that lack the TAD.…”