Identification of DPPA4 and DPPA2 as a novel family of pluripotency-related oncogenes

Po Yuan Tung, Natalia V. Varlakhanova, Paul S Knoepfler

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

In order to identify novel pluripotency-related oncogenes, an expression screen for oncogenic foci-inducing genes within a retroviral human embryonic stem cell cDNA library was conducted. From this screen, we identified not only known oncogenes but also intriguingly the key pluripo-tency factor, DPPA4 (developmental pluripotency-associated four) that encodes a DNA binding SAP domain-containing protein. DPPA4 has not been previously identified as an oncogene but is highly expressed in embryonal carcinomas, pluripotent germ cell tumors, and other cancers. DPPA4 is also mutated in some cancers. In direct transformation assays, we validated that DPPA4 is an onco-gene in both mouse 3T3 cells and immortalized human dermal fibroblasts. Overexpression of DPPA4 generates oncogenic foci (sarcoma cells) and causes anchorage-independent growth. The in vitro transformed cells also give rise to tumors in immunodeficient mice. Furthermore, functional analyses indicate that both the DNA-binding SAP domain and the histone-binding C-terminal domain are critical for the oncogenic transformation activity of DPPA4. Downregulation of DPPA4 in E14 mouse embryonic stem cells and P19 mouse embryonic carcinoma cells causes decreased cell proliferation in each case. In addition, DPPA4 overexpression induces cell proliferation through genes related to regulation of G1/S transition. Interestingly, we observed similar findings for family member DPPA2. Thus, we have identified a new family of pluripotency-related oncogenes consisting of DPPA2 and DPPA4. Our findings have important implications for stem cell biology and tumorigenesis.

Original languageEnglish (US)
Pages (from-to)2330-2342
Number of pages13
JournalStem Cells
Volume31
Issue number11
DOIs
StatePublished - 2013

Fingerprint

Oncogenes
Cell Proliferation
Embryonal Carcinoma
Genes
3T3 Cells
Neoplasms
Germ Cell and Embryonal Neoplasms
DNA
Gene Library
Sarcoma
Histones
Cell Biology
Carcinogenesis
Stem Cells
Down-Regulation
Fibroblasts
Carcinoma
Skin
Growth

Keywords

  • Cancer
  • Cancer stem cells
  • Cell cycle
  • DPPA2
  • DPPA4
  • Embryonic stem cells
  • Pluripotency-related oncogenes
  • Pluripotent stem cells

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Identification of DPPA4 and DPPA2 as a novel family of pluripotency-related oncogenes. / Tung, Po Yuan; Varlakhanova, Natalia V.; Knoepfler, Paul S.

In: Stem Cells, Vol. 31, No. 11, 2013, p. 2330-2342.

Research output: Contribution to journalArticle

Tung, Po Yuan ; Varlakhanova, Natalia V. ; Knoepfler, Paul S. / Identification of DPPA4 and DPPA2 as a novel family of pluripotency-related oncogenes. In: Stem Cells. 2013 ; Vol. 31, No. 11. pp. 2330-2342.
@article{7336fc09d7124449bca5c055262a34e8,
title = "Identification of DPPA4 and DPPA2 as a novel family of pluripotency-related oncogenes",
abstract = "In order to identify novel pluripotency-related oncogenes, an expression screen for oncogenic foci-inducing genes within a retroviral human embryonic stem cell cDNA library was conducted. From this screen, we identified not only known oncogenes but also intriguingly the key pluripo-tency factor, DPPA4 (developmental pluripotency-associated four) that encodes a DNA binding SAP domain-containing protein. DPPA4 has not been previously identified as an oncogene but is highly expressed in embryonal carcinomas, pluripotent germ cell tumors, and other cancers. DPPA4 is also mutated in some cancers. In direct transformation assays, we validated that DPPA4 is an onco-gene in both mouse 3T3 cells and immortalized human dermal fibroblasts. Overexpression of DPPA4 generates oncogenic foci (sarcoma cells) and causes anchorage-independent growth. The in vitro transformed cells also give rise to tumors in immunodeficient mice. Furthermore, functional analyses indicate that both the DNA-binding SAP domain and the histone-binding C-terminal domain are critical for the oncogenic transformation activity of DPPA4. Downregulation of DPPA4 in E14 mouse embryonic stem cells and P19 mouse embryonic carcinoma cells causes decreased cell proliferation in each case. In addition, DPPA4 overexpression induces cell proliferation through genes related to regulation of G1/S transition. Interestingly, we observed similar findings for family member DPPA2. Thus, we have identified a new family of pluripotency-related oncogenes consisting of DPPA2 and DPPA4. Our findings have important implications for stem cell biology and tumorigenesis.",
keywords = "Cancer, Cancer stem cells, Cell cycle, DPPA2, DPPA4, Embryonic stem cells, Pluripotency-related oncogenes, Pluripotent stem cells",
author = "Tung, {Po Yuan} and Varlakhanova, {Natalia V.} and Knoepfler, {Paul S}",
year = "2013",
doi = "10.1002/stem.1526",
language = "English (US)",
volume = "31",
pages = "2330--2342",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "11",

}

TY - JOUR

T1 - Identification of DPPA4 and DPPA2 as a novel family of pluripotency-related oncogenes

AU - Tung, Po Yuan

AU - Varlakhanova, Natalia V.

AU - Knoepfler, Paul S

PY - 2013

Y1 - 2013

N2 - In order to identify novel pluripotency-related oncogenes, an expression screen for oncogenic foci-inducing genes within a retroviral human embryonic stem cell cDNA library was conducted. From this screen, we identified not only known oncogenes but also intriguingly the key pluripo-tency factor, DPPA4 (developmental pluripotency-associated four) that encodes a DNA binding SAP domain-containing protein. DPPA4 has not been previously identified as an oncogene but is highly expressed in embryonal carcinomas, pluripotent germ cell tumors, and other cancers. DPPA4 is also mutated in some cancers. In direct transformation assays, we validated that DPPA4 is an onco-gene in both mouse 3T3 cells and immortalized human dermal fibroblasts. Overexpression of DPPA4 generates oncogenic foci (sarcoma cells) and causes anchorage-independent growth. The in vitro transformed cells also give rise to tumors in immunodeficient mice. Furthermore, functional analyses indicate that both the DNA-binding SAP domain and the histone-binding C-terminal domain are critical for the oncogenic transformation activity of DPPA4. Downregulation of DPPA4 in E14 mouse embryonic stem cells and P19 mouse embryonic carcinoma cells causes decreased cell proliferation in each case. In addition, DPPA4 overexpression induces cell proliferation through genes related to regulation of G1/S transition. Interestingly, we observed similar findings for family member DPPA2. Thus, we have identified a new family of pluripotency-related oncogenes consisting of DPPA2 and DPPA4. Our findings have important implications for stem cell biology and tumorigenesis.

AB - In order to identify novel pluripotency-related oncogenes, an expression screen for oncogenic foci-inducing genes within a retroviral human embryonic stem cell cDNA library was conducted. From this screen, we identified not only known oncogenes but also intriguingly the key pluripo-tency factor, DPPA4 (developmental pluripotency-associated four) that encodes a DNA binding SAP domain-containing protein. DPPA4 has not been previously identified as an oncogene but is highly expressed in embryonal carcinomas, pluripotent germ cell tumors, and other cancers. DPPA4 is also mutated in some cancers. In direct transformation assays, we validated that DPPA4 is an onco-gene in both mouse 3T3 cells and immortalized human dermal fibroblasts. Overexpression of DPPA4 generates oncogenic foci (sarcoma cells) and causes anchorage-independent growth. The in vitro transformed cells also give rise to tumors in immunodeficient mice. Furthermore, functional analyses indicate that both the DNA-binding SAP domain and the histone-binding C-terminal domain are critical for the oncogenic transformation activity of DPPA4. Downregulation of DPPA4 in E14 mouse embryonic stem cells and P19 mouse embryonic carcinoma cells causes decreased cell proliferation in each case. In addition, DPPA4 overexpression induces cell proliferation through genes related to regulation of G1/S transition. Interestingly, we observed similar findings for family member DPPA2. Thus, we have identified a new family of pluripotency-related oncogenes consisting of DPPA2 and DPPA4. Our findings have important implications for stem cell biology and tumorigenesis.

KW - Cancer

KW - Cancer stem cells

KW - Cell cycle

KW - DPPA2

KW - DPPA4

KW - Embryonic stem cells

KW - Pluripotency-related oncogenes

KW - Pluripotent stem cells

UR - http://www.scopus.com/inward/record.url?scp=84887917507&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887917507&partnerID=8YFLogxK

U2 - 10.1002/stem.1526

DO - 10.1002/stem.1526

M3 - Article

C2 - 23963736

AN - SCOPUS:84887917507

VL - 31

SP - 2330

EP - 2342

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 11

ER -