Transcriptional Blockade Induces p53-dependent Apoptosis Associated with Translocation of p53 to Mitochondria

Arima, Yoshimi; Nitta, Masayuki; Kuninaka, Shinji; Zhang, Dongwei; Fujiwara, Toshiyoshi; Taya, Yoichi; Nakao, Mitsuyoshi; Saya, Hideyuki

doi:10.1074/jbc.m410691200

Cited by 139 publications

(162 citation statements)

References 52 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…Contrary to O 6 MeG, ICLs prevent genes from being transcribed and, therefore, transcriptional inhibition could be involved. This conforms to previous findings with crosslinking agents for which transcriptional inhibition was shown to activate apoptosis (Ljungman et al, 1999;Arima et al, 2005;Goldstein et al, 2008). The question whether transcriptional inhibition has the main function in apoptosis triggered by therapeutic doses of fotemustine in melanoma cells is currently under study.…”

Section: Discussionsupporting

confidence: 66%

Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53

Naumann¹,

Roos²,

Jöst³

et al. 2009

Br J Cancer

View full text Add to dashboard Cite

Malignant melanomas are highly resistant to chemotherapy. First-line chemotherapeutics used in melanoma therapy are the methylating agents dacarbazine (DTIC) and temozolomide (TMZ) and the chloroethylating agents BCNU and fotemustine. Here, we determined the mode of cell death in 11 melanoma cell lines upon exposure to TMZ and fotemustine. We show for the first time that TMZ induces apoptosis in melanoma cells, using therapeutic doses. For both TMZ and fotemustine apoptosis is the dominant mode of cell death. The contribution of necrosis to total cell death varied between 10 and 40%. The O 6 -methylguanine-DNA methyltransferase (MGMT) activity in the cell lines was between 0 and 1100 fmol mg À1 protein, and there was a correlation between MGMT activity and the level of resistance to TMZ and fotemustine. MGMT inactivation by O 6 -benzylguanine sensitized all melanoma cell lines expressing MGMT to TMZ and fotemustine-induced apoptosis, and MGMT transfection attenuated the apoptotic response. This supports that O 6 -alkylguanines are critical lesions involved in the initiation of programmed melanoma cell death. One of the cell lines (MZ7), derived from a patient subjected to DTIC therapy, exhibited a high level of resistance to TMZ without expressing MGMT. This was related to an impaired expression of MSH2 and MSH6. The cells were not cross-resistant to fotemustine. Although these data indicate that methylating drug resistance of melanoma cells can be acquired by down-regulation of mismatch repair, a correlation between MSH2 and MSH6 expression in the different lines and TMZ sensitivity was not found. Apoptosis in melanoma cells induced by TMZ and fotemustine was accompanied by double-strand break (DSB) formation (as determined by H2AX phosphorylation) and caspase-3 and -7 activation as well as PARP cleavage. For TMZ, DSBs correlated significantly with the apoptotic response, whereas for fotemustine a correlation was not found. Melanoma lines expressing p53 wild-type were more resistant to TMZ and fotemustine than p53 mutant melanoma lines, which is in marked contrast to previous data reported for glioma cells treated with TMZ. Overall, the findings are in line with the model that in melanoma cells TMZ-induced O 6 -methylguanine triggers the apoptotic (and necrotic) pathway through DSBs, whereas for chloroethylating agents apoptosis is triggered in a more complex manner.

show abstract

Section: Discussionsupporting

confidence: 66%

Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53

Naumann¹,

Roos²,

Jöst³

et al. 2009

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…More than 50% of human cancers carry mutations in p53 (Vogelstein et al, 2000). In addition to its role as a transcription factor, p53 protein can translocate to the mitochondria in response to certain stimuli, and induces apoptosis (Arima et al, 2005). Achanta G.…”

Section: Causes For Mtdna Depletion and Deletionmentioning

confidence: 99%

Regulation of mitochondrial DNA content and cancer

Higuchi

2007

Mitochondrion

View full text Add to dashboard Cite

Enzymatic activities of the proteins encoded in nuclear genome are regulated by transcriptional, translational and post-transcriptional level. Enzymatic activities of proteins encoded in mitochondrial DNA (mtDNA) have been considered to be regulated by the same steps although detailed mechanisms might differ. However, dynamic change of the number of mtDNA, from some hundred to more than ten thousand, should be considered as another novel mechanism to regulate mtDNA-encoded proteins. Recently, we showed the connection of mtDNA depletion and deletion to cancer progression (Higuchi et al., 2006). This review focuses and describes the possible connections of the mitochondrial DNA depletion and deletion to cancer.

show abstract

“…A second mechanism involves a direct role of wild-type p53 protein at the mitochondria via proteinprotein interactions with Bcl2 family members (Marchenko et al, 2000;Sansome et al, 2001;Dumont et al, 2003;Mihara et al, 2003;Erster et al, 2004;Arima et al, 2005;Erster and Moll 2005). In response to a broad range of death stimuli like genotoxic drugs, g-irradiation, hypoxia and deregulated viral and cellular oncogenes, a fraction of induced protein rapidly (within 30-60 min) translocates to mitochondria in primary, immortal and transformed cells in culture (Marchenko et al, 2000;Sansome et al, 2001;Mihara et al, 2003;Nemajerova et al, 2005).…”

mentioning

confidence: 99%

Mitochondrially targeted wild-type p53 suppresses growth of mutant p53 lymphomas in vivo

Palacios

Moll

2006

Oncogene

View full text Add to dashboard Cite

The complex apoptotic functions of the p53 tumor suppressor are central to its antineoplastic activity in vivo. Besides its well-known action as a transcriptional activator of apoptotic genes, p53 exerts a direct proapoptotic role at the mitochondria via protein-protein interactions with Bcl2 family members, thus executing the shortest known circuitry of p53 death signaling. We recently reported that exclusive delivery of p53 to mitochondria exerts a significant in vivo tumor suppressor activity in p53-null lymphomas. However, it was unknown whether mitochondrially targeted p53 has suppressor activities in tumors harboring missense mutants, which constitute the vast majority of p53 alterations in human tumors. Here, we show that targeting p53 to mitochondria does confer a significant growth disadvantage in B-lymphomas expressing various point mutants of p53, resulting in efficient apoptosis induction in vitro and in vivo in mice.

show abstract

Transcriptional Blockade Induces p53-dependent Apoptosis Associated with Translocation of p53 to Mitochondria

Cited by 139 publications

References 52 publications

Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53

Temozolomide- and fotemustine-induced apoptosis in human malignant melanoma cells: response related to MGMT, MMR, DSBs, and p53

Regulation of mitochondrial DNA content and cancer

Mitochondrially targeted wild-type p53 suppresses growth of mutant p53 lymphomas in vivo

Contact Info

Product

Resources

About