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 pluripotency 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 oncogene 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.
authors: Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Davis, California, USA; University of California Davis Genome Center, University of California Davis, Davis, California, USA; UC Davis Comprehensive Cancer Center, Shriners Hospital For Children Northern California, Sacramento, California, USA; Institute of Pediatric Regenerative Medicine, Shriners Hospital For Children Northern California, Sacramento, California, USA.
authors: Po-Yuan
authors: PY
authors: Tung
authors: Natalia V
authors: NV
authors: Varlakhanova
authors: Paul S
authors: PS
authors: Knoepfler
mesh_terms: D016475:3T3 Cells; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors
chemical_list: D018797:Cell Cycle Proteins; C502836:DPPA2 protein, human; C519286:Dppa2 protein, mouse; C519287:Dppa4 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors
keywords: Cancer; Cancer stem cells; Cell cycle; DPPA2; DPPA4; Embryonic stem cells; Pluripotency-related oncogenes; Pluripotent stem cells
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