Apoptosis-stimulating protein of p53-2 (ASPP2/53BP2L) is an E2F target gene

Chen, D.; Padiernos, Emerson; Ding, Feiying; Lossos, Izidore S.; Lopez, Charles D.

doi:10.1038/sj.cdd.4401536

Cited by 55 publications

(49 citation statements)

References 67 publications

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“…E2F1 can also mediate apoptosis via p53-dependent and independent mechanisms. ASPP1 and ASPP2 have been identified as transcriptional targets of E2F, and increased expression of E2F-1 was shown to induce the expression of ASPP1 and ASPP2 at both mRNA and protein levels (Stanelle et al, 2002;Chen et al, 2005;Fogal et al, 2005;Hershko et al, 2005). Many tumour types exhibit defective Rb pathways and consequently an increased E2F activity.…”

Section: Aspp1 and Aspp2 Are Transcriptional Targets Of E2f1mentioning

confidence: 99%

ASPP: a new family of oncogenes and tumour suppressor genes

2007

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The apoptosis stimulating proteins of p53 (ASPP) family consists of three members, ASPP1, ASPP2 and iASPP. They bind to proteins that are key players in controlling apoptosis (p53, Bcl-2 and RelA/p65) and cell growth (APCL, PP1). So far, the best-known function of the ASPP family members is their ability to regulate the apoptotic function of p53 and its family members, p63 and p73. Biochemical and genetic evidence has shown that ASPP1 and ASPP2 activate, whereas iASPP inhibits, the apoptotic but not the cellcycle arrest function of p53. The p53 tumour suppressor gene, one of the most frequently mutated genes in human cancer, is capable of suppressing tumour growth through its ability to induce apoptosis or cell-cycle arrest. Thus, the ASPP family of proteins helps to determine how cells choose to die and may therefore be a novel target for cancer therapy.

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Section: Aspp1 and Aspp2 Are Transcriptional Targets Of E2f1mentioning

confidence: 99%

ASPP: a new family of oncogenes and tumour suppressor genes

2007

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“…Immunoprecipitations done with 2 Ag of nonimmune rabbit IgG or anti-p53 antisera overnight at 4jC. Twenty microliters of a protein A/G slurry were added and rotated at 4jC for 2 hours, beads were washed five times with lysis buffer, and immunoblotted as previously described (43).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, PCR was done with 15 ng of total DNA, 1 ACi of 3,000 Ci/mmol/L 32 P-dCTP, 200 Amol/L deoxynucleotide triphosphate (dNTP), 20 pmol primer, and 2.5 units of Taq enzyme in a 50 AL volume for 25 cycles (94jC for 10 seconds and 72jC for 15 minutes). Amplification products were resolved on 6% PAGE, imaged with autoradiography, and quantitated by scanning densitometry as previously described (43).…”

Section: Methodsmentioning

confidence: 99%

The p53 Pathway Promotes Efficient Mitochondrial DNA Base Excision Repair in Colorectal Cancer Cells

Chen

Zhu

et al. 2006

Cancer Research

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The tumor suppressor p53 plays a central role in the DNA damage response. p53 enhances base excision repair (BER), in part, through direct interaction with the repair complex. Mitochondrial DNA (mtDNA) is repaired by a mtBER pathway. Many colorectal cancers harbor mtDNA mutations that are associated with poor prognosis. In addition to modulating the apoptotic response, mitochondria-localized p53 also stimulates mtBER. However, the mechanisms by which p53 enhances colorectal cancer mtBER after stress remain unclear.To explore this, we used colorectal cancer cells isogenic for p53 (HCT116p53+/+ and HCT116p53À/À). p53+/+ cells more efficiently repaired H 2 O 2 damaged DNA in vivo as measured by semiquantitative mtDNA displacement loop PCR. Mitochondrial extracts from p53+/+ cells more efficiently stimulated 32 P-dCTP incorporation into a uracil-oligonucleotide. Recombinant p53 complemented p53À/À mitochondrial extract repair of uracil or 8-oxo-G-containing oligonucleotides. As a measure of DNA glycosylase activity, p53+/+ mitochondrial extracts more efficiently incised uracil or 8-oxo-G oligonucleotides, although recombinant p53 could not stimulate oligonucleotide incision. p53 did not influence mitochondrial apurinic/apyrimidinic endonuclease activity measured by incision of a tetrahydrofuran-oligonucleotide. p53+/+ mitochondrial extracts had higher DNA polymerase-; activity measured by 32 P-dCTP incorporation into a singlenucleotide gap oligonucleotide, and recombinant p53 complemented p53À/À mitochondrial extract DNA polymerase-; activity. mtDNA ligase activity was not affected by p53 status. p53 protein was detected in an inner mitochondrial membrane subfraction containing components of the mtBER complex. Our data suggest that an intact p53 pathway stimulates specific mtBER steps and provides mechanistic insight into the development of mtDNA mutations in colorectal cancer. (Cancer Res 2006; 66(7): 3485-94)

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“…Not surprisingly for such an important protein, control of ASPP2/ 53BP2L expression is complex and dependent on cellular context (9). Indeed, ASPP2/ 53BP2L was shown recently to be cell cycle-regulated and a direct E2F transcriptional target gene, suggesting that it functions as a common link between the Rb/E2F and p53/p73 apoptotic pathways (12). However, several observations have also suggested that post-translational mechanisms may be important for controlling ASPP2/ 53BP2L levels as changes in the magnitude of ASPP2/ 53BP2L protein levels are not always reflected by similar changes in the magnitude of mRNA levels (9,12).…”

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confidence: 99%

Control of ASPP2/53BP2L Protein Levels by Proteasomal Degradation Modulates p53 Apoptotic Function

Zhu

Ramos

Kampa

et al. 2005

Journal of Biological Chemistry

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The p53 pathway is a central mediator of the apoptotic response. ASPP2/ 53BP2L (apoptosis-stimulating protein of p53 2, also known as 53BP2L) enhances apoptosis through selective stimulation of p53 transactivation of proapoptotic target genes. Although the Rb/E2F pathway regulates ASPP2/ 53BP2L transcription, the complex mechanisms controlling ASPP2/ 53BP2L levels and function remain unknown. We now report that proteasomal degradation modulates ASPP2/ 53BP2L protein levels and apoptotic function. Treatment of cells with proteasomal inhibitors, including the clinically utilized proteasomal inhibitor bortezomib, increases ASPP2/ 53BP2L protein but not RNA levels. Likewise, anthracycline-based chemotherapy, which has multiple mechanisms of action, including proteasomal inhibition, increases ASPP2/ 53BP2L protein but not RNA levels. Proteasomal inhibition or anthracycline treatment increases ASPP2/ 53BP2L protein stability and half-life. Furthermore, the central region of the ASPP2/ 53BP2L protein is ubiquitinated as would be expected for a proteasomal substrate. More importantly, small interfering RNA knockdown of ASPP2/ 53BP2L levels attenuated bortezomib-induced apoptosis, and this effect was greater in wildtype p53 cells. Because elevated levels of ASPP2/ 53BP2L are proapoptotic, these results described an important new molecular mechanism that modulates the p53-ASPP2/ 53BP2L apoptotic pathway.

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Apoptosis-stimulating protein of p53-2 (ASPP2/53BP2L) is an E2F target gene

Cited by 55 publications

References 67 publications

ASPP: a new family of oncogenes and tumour suppressor genes

ASPP: a new family of oncogenes and tumour suppressor genes

The p53 Pathway Promotes Efficient Mitochondrial DNA Base Excision Repair in Colorectal Cancer Cells

Control of ASPP2/53BP2L Protein Levels by Proteasomal Degradation Modulates p53 Apoptotic Function

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