Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds

Kerstin M. Kampa, Jared D. Acoba, Dexi Chen, Joel Gay, Hunjoo Lee, Kelly Beemer, Emerson Padiernos, Nataya Boonmark, Zhiyi Zhu, Alice C. Fan, Alexis S. Bailey, William Fleming, Christopher Corless, Dean W. Felsher, Louie Naumovski, Charles Lopez

Research output: Contribution to journalArticle

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Abstract

The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10-17 with a neoR gene. ASPP2 -/-mice were not viable because of an early embryonic lethal event. Although ASPP2 +/- mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, γ-irra- diated 6-week-old ASPP2 +/- mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2 +/+mice. Primary thymocytes derived from ASPP2 +/- mice exhibited an attenuated apoptotic response to γ-irradiation compared with ASPP2 +/+ thymocytes. Additionally, ASPP2 +/- primary mouse embryonic fibroblasts demonstrated a defective G 0/G 1 cell cycle checkpoint after γ-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumori- genesis and response to therapy.

Original languageEnglish (US)
Pages (from-to)4390-4395
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number11
DOIs
StatePublished - Mar 17 2009

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Apoptosis
Neoplasms
Proteins
Thymocytes
Gastrin-Secreting Cells
T-Cell Lymphoma
Incidence
Cell Cycle Checkpoints
Non-Hodgkin's Lymphoma
Exons
Carrier Proteins
Carcinogenesis
Fibroblasts
Alleles
Growth
Genes
Therapeutics

ASJC Scopus subject areas

  • General

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Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds. / Kampa, Kerstin M.; Acoba, Jared D.; Chen, Dexi; Gay, Joel; Lee, Hunjoo; Beemer, Kelly; Padiernos, Emerson; Boonmark, Nataya; Zhu, Zhiyi; Fan, Alice C.; Bailey, Alexis S.; Fleming, William; Corless, Christopher; Felsher, Dean W.; Naumovski, Louie; Lopez, Charles.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 11, 17.03.2009, p. 4390-4395.

Research output: Contribution to journalArticle

Kampa, Kerstin M. ; Acoba, Jared D. ; Chen, Dexi ; Gay, Joel ; Lee, Hunjoo ; Beemer, Kelly ; Padiernos, Emerson ; Boonmark, Nataya ; Zhu, Zhiyi ; Fan, Alice C. ; Bailey, Alexis S. ; Fleming, William ; Corless, Christopher ; Felsher, Dean W. ; Naumovski, Louie ; Lopez, Charles. / Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 11. pp. 4390-4395.
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AU - Gay, Joel

AU - Lee, Hunjoo

AU - Beemer, Kelly

AU - Padiernos, Emerson

AU - Boonmark, Nataya

AU - Zhu, Zhiyi

AU - Fan, Alice C.

AU - Bailey, Alexis S.

AU - Fleming, William

AU - Corless, Christopher

AU - Felsher, Dean W.

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