ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth

Abstract

ASPP2 stimulates the apoptotic function of the p53 family in vivo. We show here that ASPP2 −/− pups died before weaning. This postnatal lethality was significantly enhanced in p53 +/− background and both deletions are synthetic lethal. ASPP2 +/− mice developed spontaneous tumors. The tumor onset was accelerated by ␥-irradiation or in p53 +/− background. Tumors derived from ASPP2 +/− mice retained wild-type ASPP2 allele even though some of them lost p53. These provide the first genetic evidence that ASPP2 is a haploinsufficient tumor suppressor that shares overlapping function(s) with p53 in mouse development and tumor suppression. ASPP2 belongs to the evolutionarily conserved ASPP (ankyrin repeats, SH3 domain, and proline-rich region containing protein) family of proteins (Samuels-Lev et al. 2001;Bergamaschi et al. 2003;Slee and Lu, 2003). ASPP2 was previously identified as an interacting partner for a number of proteins, including p53 (Iwabuchi et al. 1994), Bcl-2 (Naumovski and Cleary 1996), RelA p65 (Yang et al. 1999), Yap (Espanel andSudol 2001), APC-2(APCL) (Nakagawa et al. 2000), APP-BP1 (Chen et al. 2003), and protein phosphatase 1 (PP1) (Helps et al. 1995). All of these proteins, with the exception of APP-BP1, interact with the C-terminal region of ASPP2. The residues involved in the interactions between ASPP2 and p53 or PP1 were identified through crystal structure studies (Gorina and Pavletich 1996;Egloff et al. 1997). ASPP2 binds to the evolutionarily conserved DNAbinding domain of p53, and all ASPP2 contact residues of p53 are mutated in human cancers (Gorina and Pavletich 1996). This suggests that ASPP2/p53 interaction might have a tumor suppression function. Consistent with this, the ASPP2/p53 interaction specifically stimulates the apoptotic function of p53 (Samuels-Lev et al. 2001) and its family members p63 and p73 (Bergamaschi et al. 2004). This is achieved through the ability of ASPP2 to enhance the DNA-binding and transactivation function of p53, p63, and p73 on promoters of Bax, PIG3, and PUMA, but not on p21 waf1 nor on mdm2. The biological significance of the interaction between ASPP2 and non-p53 family proteins remains unclear. ASPP2 does not bind to the catalytic domain of PP1, although the peptide of ASPP2 containing the PP1-binding motif (RXVF) is able to inhibit the phosphatase activity of PP1 (Egloff et al. 1997). The binding of ASPP2 to APP-BP1 prevents the apoptotic function of APP-BP1 in neuronal cells by influencing the neddylation of cullin, suggesting that ASPP2 might have an antiapoptotic function in some contexts (Chen et al. 2003). The ASPP2/p65 interaction did not have a dramatic effect on the transactivation function of p65 (Yang et al. 1999).In order to provide an in vivo model system to study the biological functions of ASPP2, we generated and characterized ASPP2-deficient mice. This revealed that ASPP2 is required during the development of the brain and heart. Also, heterozygosity of ASPP2-null allele significantly accelerated tumor development. To test the biological ...

Recent Candidate Molecular Markers: Vitamin D Signaling and Apoptosis Specific Regulator of p53 (ASPP) in Breast Cancer

“…The binding of ASPP family proteins selectively modulate the apoptosis function of p53 family proteins and finally decide cell fortune between life and death (Figure 4). Furthermore, a mouse model study by Vives et al (2006) and other invitro and invivo studies by Samuels-Lev et al (2001), Bergamaschi et al (2003) and Lettre et al (2004) sustaining that ASPP1 and ASPP2 act as tumor suppressors, at the same time, iASPP as an oncogene.…”

SUMO-modified nuclear cyclin D1 bypasses Ras-induced senescence

“…Mouse embryonic fibroblasts (MEFs) are a well-established experimental system used to study oncogene-induced senescence. To investigate whether ASPP2 has a role in mediating Ras oncogene-induced senescence, MEFs were generated from ASPP2 ( þ / þ ) and ASPP2 (D3/D3) embryos, where exon 3 of the murine ASPP2 gene was deleted as previously described, 19 and infected with oncogenic H-RasV12. As expected, the expression of oncogenic H-RasV12-induced senescence in ASPP2 ( þ / þ ) MEFs was detected by the presence of the senescence marker senescence-associated b-galactosidase (SA-b-Gal), but not in ASPP2 (D3/D3) MEFs (Figure 1a and b).…”

“…Importantly, heterozygous mice of ASPP2 (D3/ þ ) and ASPP2 (D10À17/ þ ) are both prone to developing spontaneous tumors, establishing ASPP2 as a new haploinsufficient tumor suppressor. 19,20 ASPP2 expression is frequently downregulated in human tumors, and reduced ASPP2 expression is tightly associated with patients' poor prognosis. 21,22 As ASPP2 can bind other cellular proteins including p65 reticuloendotheliosis viral oncogene homolog A, B-cell lymphoma 2, protein phosphatase 1, YES-associated protein, adenomatous polyposis coli-like and amyloid-b precursor protein binding protein 1, [23][24][25][26][27][28] it is possible that ASPP2 suppresses tumor growth in ways other than promoting p53-mediated apoptosis.…”

ASPP: a new family of oncogenes and tumour suppressor genes

“…Existing studies have suggested that ASPP2 plays a central role in the regulation of apoptosis and cell growth. The most compelling evidence comes from the ASPP2 knockout mouse study (Vives et al, 2006). The group examined the role of ASPP2 in tumorigenesis and its relationship with p53 tumour suppression in homozygous or heterozygous mice lacking ASPP2 or ASPP2 and p53 alleles.…”