Role for the p53 homologue p73 in E2F-1-induced apoptosis

Irwin, Meredith S.; Marin, Maria C; Phillips, Andrew C.; Seelan, Ratnam S.; Smith, Jeremy C.; Liu, Wanguo; Flores, Elsa R.; Tsai, Kenneth Y.; Jacks, Tyler; Vousden, Karen H.; Kaelin, William G.

doi:10.1038/35036614

Cited by 659 publications

(510 citation statements)

References 28 publications

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“…E2F1 has been previously shown by us and others to activate p73 transcription by binding to E2F binding sites in the TAp73 promoter (Irwin et al, 2000;Stiewe and Pu¨tzer, 2000). In contrast, the DNp73 promoter is not activated by E2F1 Waltermann et al, 2003).…”

Section: Repression Of Telomerase Activity By P73mentioning

confidence: 75%

Regulation of telomerase activity by the p53 family member p73

Beitzinger

Oswald

Beinoraviciute-Kellner

et al. 2005

Oncogene

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The terminal ends of eukaryotic chromosomes, termed telomeres, progressively shorten during each round of cell division eventually leading cells into senescence. Tumor cells typically overcome this barrier to unlimited proliferation by activation of the human telomerase reverse transcriptase (hTERT) gene. In contrast, in most human somatic cells hTERT expression is tightly repressed by multiple tumor suppressors. Here, we studied the regulation of hTERT by the p53 family member p73. We show that forced expression of p73 or activation of endogenous p73 by E2F1 results in the downregulation of telomerase activity. Vice versa, siRNA-mediated knockdown of p73 induces hTERT expression. Responsiveness to p73 is conferred by Sp1 binding sites within the hTERT core promoter. In tumor cells, p73 isoforms lacking the transactivation domain (DNp73) are frequently overexpressed and believed to function as oncogenes. We show that DNp73 antagonizes the repressive effect of the proapoptotic p53 family members on hTERT expression and, in addition, induces hTERT expression in telomerase-negative cells by interfering with E2F-RB-mediated repression of the hTERT core promoter. These data provide evidence that the p73 gene functions as an important regulator of telomerase activity with implications for embryonic development, cellular differentiation and tumorigenesis.

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Section: Repression Of Telomerase Activity By P73mentioning

confidence: 75%

Regulation of telomerase activity by the p53 family member p73

Beitzinger

Oswald

Beinoraviciute-Kellner

et al. 2005

Oncogene

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“…Several reports have shown that DNA damage results in E2F1-mediated transcription of p73a, a p53 homolog involved in the activation of p53-responsive target genes and apoptosis (Irwin et al, 2000). As shown in Figure 6c, the sequential treatment of Cis-Nut induced a timedependent increase in p73a, whereas the treatment with Cis alone induced a slight increase above baseline.…”

Section: Nutlin-3a Induces Apoptosis In P53wt Cells and Enhances Chemmentioning

confidence: 77%

“…However, E2F1À/À knockout mice develop a broad spectrum of tumors, suggesting that E2F1 also functions as a tumor suppressor. Indeed, several authors reported that E2F1 can induce apoptosis through p53-dependent (Kowalik et al, 1995;Qin et al, 1994;Wu and Levine, 1994) and p53-independent mechanisms (Irwin et al, 2000), by upregulating apoptotic genes like Apaf-1 (Furukawa et al, 2002), p73 (Stiewe and Putzer, 2000), caspase 3 and 7 (Muller et al, 2001), Noxa and PUMA (Hershko and Ginsberg, 2004). Furthermore, forced expression of E2F1 caused increased sensitivity to DNA-damaging agents and topoisomerase II inhibition in a p53-independent manner (Nip et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

et al. 2006

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MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53À/À cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wildtype E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73a and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

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“…McKeon and coworkers [48] showed that p73 is not required for AICD induced by secondary TCR stimulation of CD4 + T cells, recovered from a Rag2 -/-reconstitution system, which argues against the general concept that p73 is essential for T cell AICD [25,36]. This suggests that p73 plays an important role in the apoptosis of the primary T cell response, but is less important for secondary responses.…”

Section: Discussionmentioning

confidence: 99%

“…p73 isoforms resulting from the usage of an alternative promoter located in the third intron lack the transactivation domain and act as dominant-negative forms (DNp73) that have antiapoptotic function [35]. The major form expressed in activated T cells is p73a [25,36].In order to investigate the mechanism of increased CD8 + T cell proliferation in SAP -/-mice, we utilized OVA-specific OT-I TCR-transgenic mice. This allowed us to further examine the activation, proliferation and apoptosis of antigen-specific CD8 + T cells on both WT and SAP -/-background.…”

mentioning

confidence: 99%

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

et al. 2007

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Defective signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is responsible for the human X-linked lymphoproliferative syndrome. Defects in T helper 2, natural killer, natural killer T and B cells have been demonstrated in SAP-deficient humans and mice, and increased proliferation of CD8 + T cells has been observed. In the current study, we investigated the properties of CD8 + T cell proliferation and activation-induced cell death (AICD), using OT-I T cell receptor (TCR)-transgenic mice on either wild-type (WT) or SAP -/-background. Interestingly, we found that ovalbumin peptide-activated SAP -/-CD8 + T cells have lower AICD compared to their WT counterparts. Furthermore, the induction of p73, a key mediator of TCRinduced apoptosis through the mitochondrial apoptotic pathway, was significantly reduced at both the mRNA and protein levels in the activated mutant cells. Meanwhile, a reduced level of activated caspase 9 was observed in the mutant cells. We conclude that reduced AICD in activated SAP -/-CD8 + T cells is associated with impaired p73 induction, indicating that the initiation of the mitochondrial apoptotic pathway might be impaired. Our data demonstrate an intrinsic defect in SAP -/-CD8 + T cells and shed light on the increased responsiveness of CD8 + T cells in SAP -/-mice. IntroductionX-linked lymphoproliferative syndrome (XLP), an abnormal immune response to EBV infection characterized by fatal infectious mononucleosis, dys-gammaglobulinemia and B cell lymphoma, is caused by mutations in the SH2D1A gene, which encodes signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) [1][2][3][4]. The adaptor SAP binds with high affinity to tyrosine motifs in the cytoplasmic domain of SLAM family immune receptors, including SLAM (CD150), CD244, CD229, SLAMF6, SLAMF7 and CD84, suggesting that SAP functions are important in modulating signals initiated by the SLAM family receptors [5][6][7][8]. It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10]. SAP is expressed in activated T, NK and NKT cells, as well as in germinal center B cells [11,12], and is indispensable for normal NKT cell development, generation of a proper Th2 response and Ig class switching in humans and mice [13][14][15][16][17][18]. In XLP patients, both EBV-infected B cells and EBVspecific CTL hyper-proliferate, although the underlying mechanism is still controversial. Previous studies with SAP -/-mice, performed by several laboratories including ours, showed an increased antigen-specific CD8 + T cell population and IFN-c production after infection with lymphocytic choriomeningitis virus (LCMV), murine c-herpesvirus 68 (MHV-68) and Toxoplasma gondii, but impaired Th2 cell differentiation and decreased IgG production [15,19,20]. In addition, we demonstrate that SAP -/-mice confer greater cytotoxic activity and increased proliferation of CD8 + T cells compared to WT mice, strongly suggesting that SAP fine-tunes th...

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Role for the p53 homologue p73 in E2F-1-induced apoptosis

Cited by 659 publications

References 28 publications

Regulation of telomerase activity by the p53 family member p73

Regulation of telomerase activity by the p53 family member p73

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

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Role for the p53 homologue p73 in E2F-1-induced apoptosis

Cited by 659 publications

References 28 publications

Regulation of telomerase activity by the p53 family member p73

Regulation of telomerase activity by the p53 family member p73

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

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Increased proliferation of CD8⁺ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death