Role of RB family on senescence

Co-Investigator: Prof Galderisi Umberto, Dr Tiziana Squillaro and Dr Nicola Alessio

Studies on senescence induced by chromatin remodelling factors and Retinoblastoma gene family members.

We have focused our attention on self-renewal, proliferation, senescence and differentiation of stem cells. Their activity is regulated by chromatin remodelling factors that operate at the highest hierarchical level. Studies on these factors can be especially important to dissect molecular pathways governing the biology of stem cells.

SWI/SNF complexes are ATP-dependent chromatin remodelling enzymes that have been shown to be required for cell cycle control, apoptosis and cell differentiation in several biological systems. The aim of our research is to investigate the role of these complexes in the biology of MSCs in particular by silencing the catalytic SWI/SNF subunit called BRG1.

SWI/SNF complexes accomplish their tasks also by interacting with members of the retinoblastoma gene family. 

 The retinoblastoma family genes RB1, RB2/P130, and P107 play a major role in controlling the cell cycle G1 /S transition through the negative regulation of the E2F family of transcription factors. In addition, this protein family plays an important role in regulating other cellular processes, such as terminal differentiation and senescence. Initial observations suggested that retinoblastoma family proteins showed overlapping functions, and initial knock-out studies suggested that Rb2/p130 and p107 had an ancillary role. However, several studies have evidenced functional differences among these proteins.  Recently, it has become clear that the role of Rb1, Rb2/p130, and p107 depends on several parameters such as animal species under investigation, cell type, and cell status (stem cell, progenitor, differentiated cell). Data on the function of retinoblastoma family members in the control of stem cell biology have been biased by the fact that the majority of authors have focused their attention mainly on the Rb1 protein. Data on the role of p107 and Rb2/p130 in stem cell biology are very scant.

Moreover, the functions of Rb1, p107, and Rb2/p130 in the biology of mesenchymal stem cells (MSCs) remain largely uncharacterized. These cells contribute significantly to the maintenance of tissue homeostasis in the body.

Consequently, any loss in numbers or the functionality of MSCs would have profound consequences for the maintenance of tissue viability. In-depth studies on the biology of MSCs also have a great therapeutic value since they are being tested in cell and gene therapy for a number of human diseases.


OUR Publications: 

1: Alessio N, Capasso S, Ferone A, Di Bernardo G, Cipollaro M, Casale F, Peluso G, Giordano A, Galderisi U. Misidentified Human Gene Functions with Mouse Models: The Case of the Retinoblastoma Gene Family in Senescence. Neoplasia. 2017 Oct;19(10):781-790. doi: 10.1016/j.neo.2017.06.005. Epub 2017 Aug 30. PubMed PMID: 28865301; PubMed Central PMCID: PMC5577395.

2: Squillaro T, Severino V, Alessio N, Farina A, Di Bernardo G, Cipollaro M, Peluso G, Chambery A, Galderisi U. De-regulated expression of the BRG1 chromatin remodeling factor in bone marrow mesenchymal stromal cells induces senescence associated with the silencing of NANOG and changes in the levels of chromatin proteins. Cell Cycle. 2015;14(8):1315-26. doi: 10.4161/15384101.2014.995053. PubMed PMID: 25724006; PubMed Central PMCID: PMC4614278.

3: Capasso S, Alessio N, Di Bernardo G, Cipollaro M, Melone MA, Peluso G, Giordano A, Galderisi U. Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation. Cell Cycle. 2014;13(3):482-90. doi: 10.4161/cc.27275. Epub 2013 Nov 26. PubMed PMID: 24281253; PubMed Central PMCID: PMC3956544.

4: Alessio N, Bohn W, Rauchberger V, Rizzolio F, Cipollaro M, Rosemann M, Irmler M, Beckers J, Giordano A, Galderisi U. Silencing of RB1 but not of RB2/P130 induces cellular senescence and impairs the differentiation potential of human mesenchymal stem cells. Cell Mol Life Sci. 2013 May;70(9):1637-51. doi: 10.1007/s00018-012-1224-x. Epub 2013 Jan 31. PubMed PMID: 23370776.

5: Helmbold H, Galderisi U, Bohn W. The switch from pRb/p105 to Rb2/p130 in DNA damage and cellular senescence. J Cell Physiol. 2012 Feb;227(2):508-13. doi: 10.1002/jcp.22786. Review. PubMed PMID: 21465484.

6: Alessio N, Squillaro T, Cipollaro M, Bagella L, Giordano A, Galderisi U. The BRG1 ATPase of chromatin remodeling complexes is involved in modulation of mesenchymal stem cell senescence through RB-P53 pathways. Oncogene. 2010 Oct 7;29(40):5452-63. doi: 10.1038/onc.2010.285. Epub 2010 Aug 9. PubMed PMID: 20697355.

7: Napolitano MA, Cipollaro M, Cascino A, Melone MA, Giordano A, Galderisi U. Brg1 chromatin remodeling factor is involved in cell growth arrest, apoptosis and senescence of rat mesenchymal stem cells. J Cell Sci. 2007 Aug 15;120(Pt 16):2904-11. Epub 2007 Jul 31. PubMed PMID: 17666433.

8: Jori FP, Galderisi U, Napolitano MA, Cipollaro M, Cascino A, Giordano A, Melone MA. RB and RB2/P130 genes cooperate with extrinsic signals to promote differentiation of rat neural stem cells. Mol Cell Neurosci. 2007 Mar;34(3):299-309. Epub 2007 Jan 12. PubMed PMID: 17223573.

9: Galderisi U, Cipollaro M, Giordano A. The retinoblastoma gene is involved in multiple aspects of stem cell biology. Oncogene. 2006 Aug 28;25(38):5250-6. Review. PubMed PMID: 16936744.

10: Jori FP, Melone MA, Napolitano MA, Cipollaro M, Cascino A, Giordano A, Galderisi U. RB and RB2/p130 genes demonstrate both specific and overlapping functions during the early steps of in vitro neural differentiation of marrow stromal stem cells. Cell Death Differ. 2005 Jan;12(1):65-77. PubMed PMID: 15459751.

11: Jori FP, Napolitano MA, Melone MA, Cipollaro M, Cascino A, Giordano A, Galderisi U. Role of RB and RB2/P130 genes in marrow stromal stem cells plasticity. J Cell Physiol. 2004 Aug;200(2):201-12. PubMed PMID: 15174090.

12: Jori FP, Galderisi U, Piegari E, Peluso G, Cipollaro M, Cascino A, Giordano A, Melone MA. RB2/p130 ectopic gene expression in neuroblastoma stem cells: evidence of cell-fate restriction and induction of differentiation. Biochem J. 2001 Dec 15;360(Pt 3):569-77. PubMed PMID: 11736646; PubMed Central PMCID: PMC1222259.

13: Galderisi U, Melone MA, Jori FP, Piegari E, Di Bernardo G, Cipollaro M, Cascino A, Peluso G, Claudio PP, Giordano A. pRb2/p130 gene overexpression induces astrocyte differentiation. Mol Cell Neurosci. 2001 Mar;17(3):415-25. PubMed PMID: 11273639.