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Apoptosis-Stimulating Protein of P53 (ASPP2) Heterozygous Mice Are Tumor-Prone and Have Attenuated Cellular Damage–Response Thresholds

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Apoptosis-Stimulating Protein of P53 (ASPP2) Heterozygous Mice Are Tumor-Prone and Have Attenuated Cellular Damage–Response Thresholds Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage–response thresholds Kerstin M. Kampaa,b, Jared D. Acobaa, Dexi Chena, Joel Gaya, Hunjoo Leea, Kelly Beemera, Emerson Padiernosa, Nataya Boonmarkc, Zhiyi Zhua, Alice C. Fanc, Alexis S. Baileya,d, William H. Fleminga,d, Christopher Corlessa, Dean W. Felsherc, Louie Naumovskic,1, and Charles D. Lopeza,2 aDepartment of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR 97239; bMedizinsche Universita¨tsklinik, Department of Hematology, Oncology, Rheumatology, Immunology, and Pulmology, Universita¨t Tu¨ bingen, Tu¨bingen 72076, Germany; cDepartments of Medicine and Pediatrics, Division of Hematology and Oncology, Stanford University, Stanford, CA 94305; and dOregon Stem Cell Center, Portland, OR 97239 Edited by Brian J. Druker, Oregon Health and Science University, Portland, OR, and approved December 30, 2008 (received for review September 11, 2008) The expression of ASPP2 (53BP2L), a proapoptotic member of a In this report, we targeted the ASPP2 allele in a mouse by family of p53-binding proteins, is frequently suppressed in many using homologous recombination to explore the in vivo con- human cancers. Accumulating evidence suggests that ASPP2 inhib- sequences of attenuated ASPP2 expression. We demonstrate its tumor growth; however, the mechanisms by which ASPP2 that reduced ASPP2 expression in heterozygous mice results suppresses tumor formation remain to be clarified. To study this, in: (i) an increased incidence of a variety of spontaneous we targeted the ASPP2 allele in a mouse by replacing exons 10–17 tumors, (ii) the accelerated formation of high-grade thymic T -with a neoR gene. ASPP2؊/؊ mice were not viable because of an cell lymphomas in ␥-irradiated mice, and (iii) after ␥-irradia early embryonic lethal event. Although ASPP2؉/؊ mice appeared tion, an attenuated apoptotic response in ASPP2ϩ/Ϫ primary ϩ/Ϫ developmentally normal, they displayed an increased incidence of thymocytes and an attenuated G0/G1 checkpoint in ASPP2 a variety of spontaneous tumors as they aged. Moreover, ␥-irra- primary mouse embryonic fibroblasts (MEFs). These data ؉/؊ diated 6-week-old ASPP2 mice developed an increased inci- provide significant insight into the observation that ASPP2 MEDICAL SCIENCES dence of high-grade T cell lymphomas of thymic origin compared expression is reduced in human cancers, and suggest a mech- with ASPP2؉/؉ mice. Primary thymocytes derived from ASPP2؉/؊ anism by which disruption of ASPP2 pathways may play a role mice exhibited an attenuated apoptotic response to ␥-irradiation in tumorigenesis and response to therapy. -compared with ASPP2؉/؉ thymocytes. Additionally, ASPP2؉/؊ pri mary mouse embryonic fibroblasts demonstrated a defective G0/G1 Results cell cycle checkpoint after ␥-irradiation. Our results demonstrate Generation of ASPP2؉/؊ Mice. To rigorously test the hypothesis that ASPP2 is a haploinsufficient tumor suppressor and, impor- that ASPP2 may have a tumor suppressor function, we targeted tantly, open new avenues for investigation into the mechanisms by ASPP2 in a mouse by using homologous recombination (Fig. which disruption of ASPP2 pathways could play a role in tumori- 1). The targeting vector was designed to disrupt exons 10–17, genesis and response to therapy. which also include codons for the ankyrin repeat and SH3 domain required for interaction with p53 family members poptosis-stimulating protein of p53-2 (ASPP2), also known (exons 14–17; Fig. 1A). The targeting vector was electropo- Aas 53BP2L, encoded by TP53BP2 (1–3), enhances dam- rated into 129/SvJ ES cells, and clones were derived by age-induced apoptosis at least in part through a p53-mediated positive–negative selection in G418/gancyclovir. Approxi- pathway (2, 4–6). Depending on cell context and type of stress, mately 250 clones were screened to identify 4 positive clones ASPP2 levels increase via transcriptional or posttranslational by Southern blot analysis (Fig. 1B). Two separate clones were mechanisms after cellular damage (4, 6). In addition to expanded and injected into C57BL/6 blastocysts to generate interacting with p53 (and family members) (5, 7), ASPP2 several highly chimeric mice. Chimeras were crossed with protein, and the 123-aa, amino-terminal, truncated splice C57BL/6 mice, and offspring were screened with 2 separate isoform 53BP2/Bbp, also known as 53BP2S (3), interacts with PCR strategies and further confirmed by Southern blot anal- several proteins involved in modulating apoptosis and cell ysis (Fig. 1 B and C). Western blot analysis using 2 different growth, including Bcl-2, p65/RelA subunit of NF-␬B, Yes- antibodies recognizing the amino terminus (anti-ASPP2 Ab1) associated protein-1, HCV core protein, APCL, and protein or the carboxy terminus (anti-ASPP2 Ab2) demonstrated an phosphatase-1 (8–13). Additionally, ASPP2 is a direct E2F approximate 2-fold reduction in ASPP2 protein levels in target gene, suggesting that it is a common link between the ASPP2ϩ/Ϫ MEFs, thymus, and liver (Fig. 1D). Rb/E2F and p53/p73 pathways (14–16). ASPP2 expression is suppressed in many human cancers, and it has been associated with poor clinical outcome in patients with aggressive non- Author contributions: K.M.K., J.D.A., D.C., J.G., H.L., N.B., A.C.F., W.H.F., L.N., and C.D.L. designed research; K.M.K., J.D.A., D.C., J.G., H.L., K.B., E.P., N.B., Z.Z., A.C.F., A.S.B., and Hodgkin’s lymphoma treated with chemotherapy (2, 17–24). C.D.L. performed research; D.W.F. contributed new reagents/analytic tools; K.M.K., J.D.A., These findings suggest that ASPP2 is involved in important D.C., J.G., H.L., N.B., Z.Z., A.C.F., W.H.F., C.C., D.W.F., L.N., and C.D.L. analyzed data; and tumor suppression networks and the cellular damage response. K.M.K. and C.D.L. wrote the paper. Overexpression of ASPP2 or Bbp/53BP2S can suppress E1A The authors declare no conflict of interest. and ras-mediated transformation of rat embryo fibroblasts (25, This article is a PNAS Direct Submission. 26), whereas attenuation of ASPP2 expression promotes clo- 1Present address: Genentech Inc., 1 DNA Way, South San Francisco, CA. nogenic survival and inhibits apoptosis in cell culture (2, 4, 6) 2To whom correspondence should be addressed. E-mail: [email protected]. and promotes tumor formation in vivo (27). However, the This article contains supporting information online at www.pnas.org/cgi/content/full/ mechanisms by which reduced ASPP2 expression enhances 0809080106/DCSupplemental. tumor formation in vivo remain to be elucidated. © 2009 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809080106 PNAS Early Edition ͉ 1of6 Downloaded by guest on October 6, 2021 Fig. 1. Generation of ASPP2ϩ/Ϫ mice. (A) Schema of ASPP2 allele and targeting vector. Black boxes indicate coding exons; white boxes indicate untranslated regions. Neo indicates neomycin resistance gene; TK indicates thymidine kinase gene. (B) Strategies for detecting a wild-type ASPP2 allele (Upper) or integration of the targeting vector (Lower). Probe locations for Southern blot analysis are shown as gray bars. Open arrows indicate PCR set 1 primers. Neo-PCR indicates NeoR gene amplicon. WT-PCR indicates ASPP2 exon 13 amplicon. (C) Genotyping using PCR (Upper) and Southern blot analysis (Lower). (D) Western blots on equivalent amounts of total protein from ASPP2ϩ/Ϫ and ASPP2ϩ/ϩ MEFs (Upper), or thymuses and livers (Lower), using anti-ASPP2 Ab1 or anti-ASPP2 Ab2. Fold-expression (relative to ϩ/ϩ) normalized to tubulin. ASPP2؊/؊ Mice Are Not Viable Because of an Embryonic Lethal Event. expression in available tumors arising in heterozygous mice did Although ASPP2ϩ/Ϫ mice appeared normal and reproduced, we not reveal loss of expression by quantitative RT-PCR (Fig. S1) could not identify viable ASPP2Ϫ/Ϫ pups. Genotyping of new- or by Western blot analysis (Fig. S2). To further explore whether born litters demonstrated an increased frequency of ASPP2ϩ/ϩ ASPP2 cooperated with p53 to suppress tumor development, we and ASPP2ϩ/Ϫ pups over the expected frequencies, consistent generated ASPP2ϩ/Ϫ;p53ϩ/Ϫ and ASPP2ϩ/ϩ;p53ϩ/Ϫ mice and with an embryonic lethal defect (Fig. 2). We performed timed determined the incidence of tumor formation as they aged. harvests as early as embryonic day 6.5 but were unsuccessful in Although, as expected (28), loss of a p53 allele increased the characterizing ASPP2Ϫ/Ϫ embryos. To explore whether the incidence of spontaneous tumors, we found that an ASPP2ϩ/Ϫ lethal ASPP2Ϫ/Ϫ phenotype could be altered, we generated background did not further accelerate tumorigenesis in p53ϩ/Ϫ ASPP2ϩ/Ϫ;p53ϩ/Ϫ mice and intercrossed them. However, we mice (Fig. S3). could not produce ASPP2Ϫ/Ϫ mice or embryos, regardless of the background p53 genotype, nor could we produce them in an ASPP2؉/؊ Mice Have an Increased Incidence of ␥-Irradiation-Induced inbred BALB/c background. High-Grade Lymphomas. Because ASPP2 is damage-inducible (2, 4, 6) and has a tumor-suppression function (Fig. 3), we reasoned ASPP2؉/؊ Mice Have an Increased Incidence of Spontaneous Tumors. that ASPP2ϩ/Ϫ mice would demonstrate an increased incidence Because human cancers can have reduced ASPP2 levels (2, of ␥-irradiation-induced tumors. To examine this, we ␥-irradi- 17–24), we determined the spontaneous tumor-free survival of ated 6-week-old ASPP2ϩ/ϩ and ASPP2ϩ/Ϫ mice with a total of 6.0 ASPP2ϩ/Ϫ mice over an extended period (Fig. 3A). ASPP2ϩ/ϩ Gy or 10.5 Gy (in divided weekly fractions) and measured the mice demonstrated the expected incidence of spontaneous tu- tumor-free survival (Fig. 4A). ASPP2ϩ/ϩ mice did not develop mors seen in mice of similar background strain (28). In contrast, tumors during the observed time. However, ASPP2ϩ/Ϫ mice ASPP2ϩ/Ϫ mice had a significant increase in tumor formation developed tumors after 6.0-Gy or 10.5-Gy irradiation (P ϭ 0.024 (P ϭ 0.011, log-rank test).
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