Basilico Lab - Microbiology
Claudio Basilico M.D.
Jan T. Vilcek Professor of Molecular Pathogenesis
Medical Science Building, Room 256
550 First Avenue, New York, NY 10016
Office: (212) 263-5341
Fax: (212) 263-8714
Lab: (212) 263-5331
Education and General Information
Dr. Basilico received an M.D. degree from the University of Milan, and the "Libera Docenza" in Microbiology from the Italian Ministry of Education in 1969. After postdoctoral training at the California Institute of Technology, International Laboratory of Genetics and Biophysics in Naples, and the Albert Einstein College of Medicine in New York, he became an Assoc. Prof. of Pathology at NYU School of Medicine in 1970. In 1976 he was promoted to Professor of Pathology and in 1990 he became Professor and Chairman of the Dept. of Microbiology.
Throughout his career, Dr. Basilico's research interests have focused on the mechanisms regulating cell proliferation and differentiation. He has contributed important work on the molecular biology of oncogenic viruses, gene expression and cell cycle progression in animal cells, and signal transduction by growth factors and their receptors.
Basilico Lab Research Interests
Signals Controlling Cell Proliferation and Differentiation.
The major interest of my laboratory is the control of proliferation in normal and cancer cells and the genes and gene-products whose interplay regulates proliferation and differentiation.
To understand how growth factor signaling promotes cell proliferation and differentiation, we are studying the mechanism of action and the regulation of expression of fibroblast growth factors (FGF). FGF represents a large family of growth factors which signal through their interaction with tyrosine kinase receptors (FGFR) which also make-up a gene family. FGF signaling plays a major role in a variety of developmental processes. Ectopic or excessive FGF expression can lead to oncogenesis. The main projects presently being carried out focus on the regulation of skeletal development by FGF signaling. Unregulated FGF signaling, due to FGFR activating mutations, causes a variety of dominant bone morphogenetic disorders in humans, including several forms of dwarfism and craniosynostosis syndromes. Excessive FGF signaling alters bone development by affecting the dynamics of growth and differentiation of chondrocytes and osteoblasts, the two major cell types involved in bone formation. We are studying the biological response of these two cell types to FGF and the key pathways involved in this process.
In chondrocytes, we found that FGF signaling inhibits proliferation and increases apoptosis both in vitro and in vivo. These effects are cell type-specific and provide a logical explanation of why excessive FGF signaling causes dwarfism and chondrodysplastic syndromes. We aim at identifying the key factors that direct the FGF response of chondrocytes to growth inhibitory pathways. We have shown that FGF-induced growth arrest requires the activity of two Retinoblastoma (Rb) family members, p107 and p130, but not Rb itself. One of the earliest distinguishing events following FGF treatment is the very rapid dephosphorylation of p107. We have shown that p107 dephosphorylation is a critical early event in the growth-inhibitory response of these cells to FGF signaling and that the PP2A phosphatase targets p107 for dephosphorylation in FGF-treated chondrocytes. We have recently identified the regulatory subunit of PP2A that targets this enzyme to p107.
Immature osteoblasts respond to FGF with increased proliferation. Sustained FGF signaling inhibits differentiation. We have examined the program of gene expression in osteoblasts expressing activated FGFR mutants and detected a significant down-regulation of Wnt target gene expression. Concomitantly, we have observed a dramatic induction of expression of Sox2, a transcription factor of the HMG domain family, whose expression is a classical marker of embryonic stem cells. Sox2 is also induced by FGF treatment of normal osteoblasts and is clearly detectable in cranial osteoblasts in vivo. Wnt signaling promotes osteoblast function and high bone mass in humans and mice and thus inhibition of Wnt signaling is likely to be one important mechanism by which FGFs inhibit osteoblast differentiation. Our results showed that FGF utilizes multiple mechanisms to inhibit Wnt-induced transcription in osteoblasts and that Sox2 induction plays a major role.
While investigating the role of Sox2 induction in the osteoblast response to FGF we have made the exciting discovery that Sox2 is required for self-renewal of the osteoblast lineage. Inactivation of Sox2 in cultured osteoblasts abolish proliferation capacity and cause these cells to enter a senescent-like phenotype. Conditional KO of Sox2 in the osteoblast lineage in mice produces animals which are small, osteopenic and have low bone density. Sox2 is highly expressed in osteospheres, thought to represent multipotent or unipotent stem cells in the osteoblast lineage. Sox2 maintains a proliferative stem-like state in osteoblasts by activating transcription of critical target “stemness” genes and by inhibiting the activity of the prodifferentiation Wnt pathway using both transcriptional and post-transcriptional mechanisms. Importantly, Sox2 plays a similar role in osteosarcomas, where Sox2 downregulation abolishes tumorigenicity, promotes osteogenic differentiation and activate the Wnt pathway. This suggests that in these tumors, high Sox2 expression sustains a population of cancer stem cells.
We have identified most of the genes that are bound and regulated by Sox2 in osteoprogenitor as well as in osteosarcoma cells. In addition to genes involved in proliferation and stemness, we have found that Sox2 antagonizes the tumor suppressive hippo pathway by targeting and regulating three important genes in the pathway, YAP, Merlin (NF2) and Kibra (WWC1). As a consequence, hippo pathway activity is low in osteosarcoma stem cells, and becomes active in their more differentiated descendants, which can undergo osteogenic differentiation. Complementation experiments show that antagonism of the hippo pathway is one of the main mechanisms by which Sox2 maintains stemness in the osteoblast lineage as well as in osteosarcomas.
Isolation and analysis of DNA derived from nucleosome-free regions.
Murtha, M., Wang, Y., Basilico, C., Dailey, L.
Methods Mol Biol. 2013;977:35-51. PMID: 23436352
The B55 alpha regulatory subunit of Protein Phosphatase 2A mediates FGF-induced p107 dephosphorylation and growth arrest in chondrocytes.
Kolupaeva V, Daempfling L, Basilico C.
Mol Cell Biol. 2013 Aug;33(15):2865-78. PMID: 23716589
Sox2 regulates YAP1 to maintain stemness and determine cell fate in the osteo-adipo lineage.
Seo E., Basu-Roy U., Gunaratne P. H., Coarfa C., Lim DS, Basilico C., Mansukhani A.
Cell Reports, 2013 Jun 27;3(6):2075-87. PMID: 23791527
Overexpression of cyclin E/CDK2 complexes overcomes FGF-induced cell cycle arrest in the presence of hypophosphorylated Rb proteins.
Kolupaeva V, Basilico C.
Cell Cycle. 2012 Jul 1;11(13):2557-66. PMID: 22713240
Mesodermal expression of Fgfr2S252W is necessary and sufficient to induce craniosynostosis in a mouse model of Apert syndrome.
Holmes G, Basilico C.
Dev Biol. 2012 Aug 15;368(2):283-93. PMID: 22664175
Perspectives on cancer stem cells in osteosarcoma.
Basu-Roy U, Basilico C, Mansukhani A.
Cancer Lett. 2012 May 29. [Epub ahead of print]
Regulation of cranial morphogenesis and cell fate at the neural crest-mesoderm boundry by engrailed 1.
Deckelbaum RA, Holmes G, Zhao Z, Tong C, Basilico C, Loomis CA.
Development. 2012 Apr;139(7):1346-58. PMID: 22395741
Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage.
Seo E, BasuRoy U, Zavadil J, Basilico C, Mansukhani A.
Mol Cell Biol.
2011 Nov 31: 4593-4608.
Sox2 maintains tumor initiating cells in osteosarcoma.
Basu-Roy U, Seo E, Ramanathapuram L, Rapp TB, Perry J, Orkin, S, Mansukhani A and Basilico C (2011)
Oncogene. 2012 May 3;31(18):2270-82. PMID: 21927024
The Transcription Factor Sox2 is Required for Osteoblast Self-renewal.
Basu-Roy, U., Ambrosett,i D., Favaro, R., Nicolis, SK., Manukhani, A., Basilico, C. (2010).
Cell Death and Differentiation. 17(8):1345-53.
Early Onset of Craniosynostosis in an Apert Mouse Model Reveals Critical Features of this Pathology.
Holmes G., Rotschild G., Basu Roy U., Deng C-X., Mansukhani A., Basilico, C. (2009).
Dev Biol. 2009 328(2):273-84. PMID: 19389359
PP2A-mediated Dephosphorylation of p107 Plays a Critical Role in Chondrocyte Cell Cycle Arrest by FGF.
Kolupaeva V, Laplantine E, and Basilico C. (2008).
PLoS ONE 3(10) e3447 PMID: 18927618
Identification of Active Transcriptional Regulator Modules by the Functional Assay of DNA from Nucleosome-free Regions.
Yaragatti, M., Basilico, C., Dailey, L., (2008).
Genome Research 18(6):930-8. PMID: 18441229
Fibroblast Growth Factor Signaling uses Multiple Mechanisms to Inhibit Wnt-induced Transcription in Osteoblasts.
Ambrosetti, D., Holmes, G., Mansukhani, A., Basilico, C. (2008).
Mol Cell Biol. 28(15):4759-71. PMID: 18505824
Mechanisms Underlying Differential Responses to FGF Signaling.
Dailey, L., Ambrosetti, D., Mansukhani, A., Basilico, C. (2005).
Cytokine & Growth Factor Reviews 16:233-247.
A Network of Transcriptional and Signaling Events Activated by FGF to Induce Chondrocyte Growth Arrest and Differentiation.
Dailey, L., Laplantine, E., Priore, R., and Basilico, C. (2003).
J. Cell Biol. 161:1053-1066. PMID: 12821644
STAT1 Mediates the Increased Apoptosis and Reduced Chondrocyte Proliferation of Mice Overexpressing FGF2.
Sahni, M., Raz, R., Coffin, J.D., Levy, D., and Basilico, C. (2001).
Development 129:2119-2129, 2001.
Compensation by FGF1 does not Account for the Mild Phenotypic Defects Observed in FGF2 Null Mice.
Miller, D.L., Ortega, S., Bashayan, O., Basch, R. and Basilico, C. (2000).
Mol. Cell. Biol. 20:2260-2268. PMID: 10688672
Modulation of the Activity of Multiple Transcriptional Activation Domains by the DNA Binding Domains Mediates the Synergistic Action of SOX2 and Oct-3 on the Fibroblast Growth Factor-4 enhancer.
Ambrosetti, D-C., Scholer, H.R., Dailey, L., and Basilico, C. (2000).
J. Biol. Chem. 275:23387-23397. PMID: 10801796
FGF Signaling Inhibits Chondrocyte Proliferation and Regulates Bone Development through STAT1 Pathway.
Sahni, M., Ambrosetti, D., Mansukhani, A., Gertner, R., Levy, D., and Basilico, C. (1999).
Genes & Dev. 13:1361-1366. PMID: 10364154
Neuronal Defects and Delayed Wound Healing in Mice Lacking Fibroblast Growth Factor 2.
Ortega, S., Ittmann, M., Tsang, S.H., Ehrlich, M., and Basilico, C. (1998).
Proc. Natl. Acad. Sci. USA 95:5672-5677. PMID: 9576942
Developmental-specific Activity of the FGF-4 Enhancer Requires the Synergistic Action of Sox2 and Oct-3.
Yuan, H., N., Basilico, C., and Dailey, L. (1995).
Genes & Development 9:2635-2645. PMID: 7590241
LAB MEMBERS: Lisa Dailey, Victoria Kolupaeva, Alka Mansukhani, Matthew Murtha, Upal Basu-Roy, Eugenia Han, Rachel Ruoff.