Induction of apoptotic genes by a p73-phosphatase and tensin homolog (p73-PTEN) protein complex in response to genotoxic stress

Jason A. Lehman, David L. Waning, Christopher N. Batuello, Rocky Cipriano, Madhavi P. Kadakia, Lindsey Mayo

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The p53 family member, p73, has been characterized as a tumor suppressor and functions in a similar manner as p53 to induce cellular death. The phosphatase and tensin homolog (PTEN) can function as a dual specificity lipid/protein phosphatase. However, recent data have described multiple roles for nuclear PTEN independent of its lipid phosphatase activity. PTEN can directly or indirectly activate p53 to promote apoptosis. We examined whether PTEN would interact and regulate p73 independent of p53. Co-localization in the nucleus and complex formation of p73/PTEN were observed after DNA damage. Furthermore, we also demonstrate that p73α/PTEN proteins directly bind one another. Both overexpressed and endogenous p73-PTEN interactions were determined to be the strongest in the nuclear fraction after DNA damage, which suggested formation of a transcriptional complex. We employed chromatin immunoprecipitation (ChIP) and found that p73 and PTENwere associated with thePUMApromoter after genotoxic stress in TP53-null cells. We found that another p73 target, BAX, had an increased expression in the presence of p73 and PTEN. In addition, in virus-transduced cell lines stably expressing p73, PTEN, or both p73/PTEN, we found that the p73/PTEN cells were more sensitive to genotoxic stress and cellular death as measured by increased poly(ADP-ribose) polymerase cleavage and PUMA/Bax induction. Conversely, knockdown of PTEN dramatically reduced Bax and PUMA levels. Thus, a p73-PTEN protein complex is engaged to induce apoptosis independent of p53 in response to DNA damage.

Original languageEnglish
Pages (from-to)36631-36640
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number42
DOIs
StatePublished - Oct 21 2011

Fingerprint

Phosphoric Monoester Hydrolases
DNA Damage
Genes
Proteins
Tensins
DNA
Apoptosis
Lipids
Null Lymphocytes
Poly(ADP-ribose) Polymerases
Chromatin Immunoprecipitation
Phosphoprotein Phosphatases
Viruses
Chromatin
Tumors
Cells

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Induction of apoptotic genes by a p73-phosphatase and tensin homolog (p73-PTEN) protein complex in response to genotoxic stress. / Lehman, Jason A.; Waning, David L.; Batuello, Christopher N.; Cipriano, Rocky; Kadakia, Madhavi P.; Mayo, Lindsey.

In: Journal of Biological Chemistry, Vol. 286, No. 42, 21.10.2011, p. 36631-36640.

Research output: Contribution to journalArticle

Lehman, Jason A. ; Waning, David L. ; Batuello, Christopher N. ; Cipriano, Rocky ; Kadakia, Madhavi P. ; Mayo, Lindsey. / Induction of apoptotic genes by a p73-phosphatase and tensin homolog (p73-PTEN) protein complex in response to genotoxic stress. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 42. pp. 36631-36640.
@article{30cca02b863f476c8c2ba2f9753d4494,
title = "Induction of apoptotic genes by a p73-phosphatase and tensin homolog (p73-PTEN) protein complex in response to genotoxic stress",
abstract = "The p53 family member, p73, has been characterized as a tumor suppressor and functions in a similar manner as p53 to induce cellular death. The phosphatase and tensin homolog (PTEN) can function as a dual specificity lipid/protein phosphatase. However, recent data have described multiple roles for nuclear PTEN independent of its lipid phosphatase activity. PTEN can directly or indirectly activate p53 to promote apoptosis. We examined whether PTEN would interact and regulate p73 independent of p53. Co-localization in the nucleus and complex formation of p73/PTEN were observed after DNA damage. Furthermore, we also demonstrate that p73α/PTEN proteins directly bind one another. Both overexpressed and endogenous p73-PTEN interactions were determined to be the strongest in the nuclear fraction after DNA damage, which suggested formation of a transcriptional complex. We employed chromatin immunoprecipitation (ChIP) and found that p73 and PTENwere associated with thePUMApromoter after genotoxic stress in TP53-null cells. We found that another p73 target, BAX, had an increased expression in the presence of p73 and PTEN. In addition, in virus-transduced cell lines stably expressing p73, PTEN, or both p73/PTEN, we found that the p73/PTEN cells were more sensitive to genotoxic stress and cellular death as measured by increased poly(ADP-ribose) polymerase cleavage and PUMA/Bax induction. Conversely, knockdown of PTEN dramatically reduced Bax and PUMA levels. Thus, a p73-PTEN protein complex is engaged to induce apoptosis independent of p53 in response to DNA damage.",
author = "Lehman, {Jason A.} and Waning, {David L.} and Batuello, {Christopher N.} and Rocky Cipriano and Kadakia, {Madhavi P.} and Lindsey Mayo",
year = "2011",
month = "10",
day = "21",
doi = "10.1074/jbc.M110.217620",
language = "English",
volume = "286",
pages = "36631--36640",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "42",

}

TY - JOUR

T1 - Induction of apoptotic genes by a p73-phosphatase and tensin homolog (p73-PTEN) protein complex in response to genotoxic stress

AU - Lehman, Jason A.

AU - Waning, David L.

AU - Batuello, Christopher N.

AU - Cipriano, Rocky

AU - Kadakia, Madhavi P.

AU - Mayo, Lindsey

PY - 2011/10/21

Y1 - 2011/10/21

N2 - The p53 family member, p73, has been characterized as a tumor suppressor and functions in a similar manner as p53 to induce cellular death. The phosphatase and tensin homolog (PTEN) can function as a dual specificity lipid/protein phosphatase. However, recent data have described multiple roles for nuclear PTEN independent of its lipid phosphatase activity. PTEN can directly or indirectly activate p53 to promote apoptosis. We examined whether PTEN would interact and regulate p73 independent of p53. Co-localization in the nucleus and complex formation of p73/PTEN were observed after DNA damage. Furthermore, we also demonstrate that p73α/PTEN proteins directly bind one another. Both overexpressed and endogenous p73-PTEN interactions were determined to be the strongest in the nuclear fraction after DNA damage, which suggested formation of a transcriptional complex. We employed chromatin immunoprecipitation (ChIP) and found that p73 and PTENwere associated with thePUMApromoter after genotoxic stress in TP53-null cells. We found that another p73 target, BAX, had an increased expression in the presence of p73 and PTEN. In addition, in virus-transduced cell lines stably expressing p73, PTEN, or both p73/PTEN, we found that the p73/PTEN cells were more sensitive to genotoxic stress and cellular death as measured by increased poly(ADP-ribose) polymerase cleavage and PUMA/Bax induction. Conversely, knockdown of PTEN dramatically reduced Bax and PUMA levels. Thus, a p73-PTEN protein complex is engaged to induce apoptosis independent of p53 in response to DNA damage.

AB - The p53 family member, p73, has been characterized as a tumor suppressor and functions in a similar manner as p53 to induce cellular death. The phosphatase and tensin homolog (PTEN) can function as a dual specificity lipid/protein phosphatase. However, recent data have described multiple roles for nuclear PTEN independent of its lipid phosphatase activity. PTEN can directly or indirectly activate p53 to promote apoptosis. We examined whether PTEN would interact and regulate p73 independent of p53. Co-localization in the nucleus and complex formation of p73/PTEN were observed after DNA damage. Furthermore, we also demonstrate that p73α/PTEN proteins directly bind one another. Both overexpressed and endogenous p73-PTEN interactions were determined to be the strongest in the nuclear fraction after DNA damage, which suggested formation of a transcriptional complex. We employed chromatin immunoprecipitation (ChIP) and found that p73 and PTENwere associated with thePUMApromoter after genotoxic stress in TP53-null cells. We found that another p73 target, BAX, had an increased expression in the presence of p73 and PTEN. In addition, in virus-transduced cell lines stably expressing p73, PTEN, or both p73/PTEN, we found that the p73/PTEN cells were more sensitive to genotoxic stress and cellular death as measured by increased poly(ADP-ribose) polymerase cleavage and PUMA/Bax induction. Conversely, knockdown of PTEN dramatically reduced Bax and PUMA levels. Thus, a p73-PTEN protein complex is engaged to induce apoptosis independent of p53 in response to DNA damage.

UR - http://www.scopus.com/inward/record.url?scp=80054706894&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80054706894&partnerID=8YFLogxK

U2 - 10.1074/jbc.M110.217620

DO - 10.1074/jbc.M110.217620

M3 - Article

C2 - 21873427

AN - SCOPUS:80054706894

VL - 286

SP - 36631

EP - 36640

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 42

ER -