Misidentified Human Gene Functions with Mouse Models: The Case of the Retinoblastoma Gene Family in Senescence
Authors: Fiorina Casale
Umberto Galderisi
Angela Ferone
Antonio Giordano
Giovanni Di Bernardo
Stefania Capasso
Nicola Alessio
Gianfranco Peluso
Marilena Cipollaro
Journal: Neoplasia (2017)
Discipline: CLINICAL MEDICINE
Keywords: mice models; orthologous genes; paralogous genes; retinoblastoma gene family; cell cycle
Affiliations: Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania "Luigi Vanvitelli", Naples, Italy., Dipartimento della Donna, del Bambino e di Chirurgia Generale e Specialistica, University of Campania "Luigi Vanvitelli", Naples, Italy., Institute of Bioscience and Bioresources, CNR, Naples, Italy., Sbarro Institute for Cancer Research and Molecular Medicine and Department of Biology, College of Science and Technology, Temple University, Philadelphia PA; Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy., Sbarro Institute for Cancer Research and Molecular Medicine and Department of Biology, College of Science and Technology, Temple University, Philadelphia PA; Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania "Luigi Vanvitelli", Naples, Italy; Institute of Bioscience and Bioresources, CNR, Naples, Italy. Electronic address: .

Abstract:  Although mice models rank among the most widely used tools for understanding human genetics, biology, and diseases, differences between orthologous genes among species as close as mammals are possible, particularly in orthologous gene pairs in which one or more paralogous (i.e., duplicated) genes appear in the genomes of the species. Duplicated genes can possess overlapping functions and compensate for each other. The retinoblastoma gene family demonstrates typical composite functionality in its three member genes (i.e., RB1, RB2/P130, and P107), all of which participate in controlling the cell cycle and associated phenomena, including proliferation, quiescence, apoptosis, senescence, and cell differentiation. We analyzed the role of the retinoblastoma gene family in regulating senescence in mice and humans. Silencing experiments with each member of the gene family in mesenchymal stromal cells (MSCs) and fibroblasts from mouse and human tissues demonstrated that RB1 may be indispensable for senescence in mouse cells, but not in human ones, as an example of species specificity. Furthermore, although RB2/P130 seems to be implicated in maintaining human cell senescence, the function of RB1 within any given species might differ by cell type, as an example of cell specificity. For instance, silencing RB1 in mouse fibroblasts induced a reduced senescence not observed in mouse MSCs. Our findings could be useful as a general paradigm of cautions to take when inferring the role of human genes analyzed in animal studies and when examining the role of the retinoblastoma gene family in detail. 

Retracted: No

PubPeer comments:
 There appear to be some image overlaps within Figure 2 in this paper (green box, after rotation) and between this paper and two other papers. The first and last author appears on all three papers that are involved. Some authors, Antonio Giordano, for example only appear on a single paper. Figure 1c, eLife (2020), doi: 10.7554 elife.54523, Received: 17 December 2019, https: pubpeer.com publications 8B51589E5BECC6E5EDBDE25B9F4EFE Figure 2, Neoplasia (2017), doi: 10.1016 j.neo.2017.06.005, Received 1 April 2017, https: pubpeer.com publications 128BEF59CE331E3BB55727E243FBA8 Figure 2 excerpt, Oncotarget (2015), doi: 10.18632 oncotarget.6277 Received: 10 September 10 2015, https: pubpeer.com publications C74A8C7AA46F3D00D393675E20A0C6 *** ![file] ,