Stephen Jones, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Cancer Biology
   Cell Biology

Other Affiliation(s):
   Interdisciplinary Graduate Program

Genes In Development and Tumorigenesis

Failure to properly regulate cell differentiation and proliferation can lead to aberrant development and/or cancer. Our laboratory creates genetically-modified mice to investigate the regulatory pathways governing normal cell growth and development, and to examine how alteration of these pathways leads to tumorigenesis. The use of genetically-defined mice and of cells derived from these mice permits analysis of the growth regulatory properties of genes to be performed in minimally-perturbed experimental systems. We are presently focusing our attention on the proto-oncogenes Mdm2 and Wnt5a.

The Mdm2 gene is amplified to high copy numbers in approximately one-third of all human sarcomas, and is overexpressed in a wide range of human cancers. The Mdm2 protein forms a complex with the p53 tumor suppressor protein, and work from our laboratory utilizing Mdm2-deficient mice and cells derived from these mice has demonstrated that Mdm2 plays a critical role in regulation of normal cell growth and development, primarily by binding to p53 and targeting p53 for proteosome degradation. Transgenic mice which overexpress Mdm2 undergo tumor formation, and the spectrum of tumor types present in these mice indicates that a p53-independent pathway to tumorigenesis is invoked by Mdm2 when Mdm2 is overexpressed. We are currently performing experiments to elucidate this mechanistic pathway to tumorigenesis.

Wnt5a is a member of the Wnt family of secreted glycoproteins which function as paracrine or autocrine signals to regulate growth control and tissue patterning. We have created mice deficient for Wnt5a in order to investigate the role of Wnt5a in development. Analysis of these mice indicates that Wnt5a is required for proper formation of the posterior axis and of other structures derived from the mesodermal precursors originating in the caudal portion of the embryo. These findings highlight the importance of Wnt5a in proper gastrulation. In addition, we have found that mice heterozygous for functional Wnt5a are susceptible to lymphoma. Characterization of the role of Wnt5a in control of cell proliferation is presently ongoing.

Figure

Skeletal abnormalities in Wnt5a-deficient mice. The null mice fail to form the nasal and premaxilla region of the skull, display fused thoracic vertebrae and fused or absent sacral and caudal vertebrae, possess an open and malformed sternum, bifurcated ribs, and display a misshapen and reduced pelvis. In addition, the forelimbs and hindlimbs of these Wnt5a-deficient mice are grossly foreshortened.

Selected References

Mudhasani, R., Zhu, Z., Hutvagner, G., Eischen, C.M., Lyle, S., Hall, L., Lawrence  , J., Imbalzano, A.N. and Jones, S.N. (2008) Loss of miRNA biogenesis induces p19-p53 signaling and senescence in primary cells. J. Cell. Biol . 181:1055-1063.

Matijasevic, Z., Steinman, H.A., Hoover  , K. and Jones, S.N. (2008) Mdm4 suppresses transformation and tumorigenesis in p53-deficient cells and mice by preventing spindle multipolarity and chromosome loss. Mol. Cell. Biol .  28:1265-1273.

Coles, A.H., Liang, H., Zhu, Z., Marfella, C., Kang, J., Imbalzano, A.N., and Jones, S.N. (2007) Deletion of p37^Ing1 in mice reveals a p53-independent role for Ing1 in suppression of cell proliferation, apoptosis, and tumorigenesis. Cancer Res . 67:2054-2061.

Lu, X., Ma. O., Ngyuen, T-A., Jones, S.N., Oren, M., and Donehower, L.A.  (2007) The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 12:342-354.

Liang, H., Coles, A.H., Zayas, ZJ, Jurecic, R., Kang, J. and Jones, S.N. (2007) Non-cannonical Wnt promotes apoptosis in thymocyte development. J. Exp. Med . 204:3077-3084.

Lengner, C.J., Steinman, H.A., Gagnon, J., Smith, T.W., Henderson  , J.E., Kream B.E., Stein, G.S., Lian, J.B. and Jones, S.N. (2006). Osteoblast differentiation and skeletal development are regulated by Mdm2-p53 signaling.  J. Cell Biol. 172:909-921.

Guidi, C., Mudhasani. R., Hoover , K.,  Koff, A., Leav, I., Imbalzano, T., and Jones, SN. (2006) Functional interaction of the Rb and Ini1/Snf5 tumor suppressors in cell growth and pituitary tumorigenesis.   Cancer Res. 66:8076-8082.

Imbalzano, A.N., and Jones, S.N. (2005). Snf5 tumor suppressor couples chromatin remodeling, checkpoint control, and chromosomal stability. Cancer Cell 7:294-295.

Steinman, H.A, Hoover  , K, Sands, A.T. and Jones, S.N. (2005). Rescue of Mdmx deficient mice by Mdm2 reveals overlapping functions of Mdm2 and Mdm4 during development. Oncogene 24:7935-7940.

Steinman, H., Burstein, E., Lengner, C., Gosselin, J., Pihan, G., Duckett, C.S. and Jones, S.N. (2004). An alternative splice form of Mdm2 induces p53-independent cell growth and tumorigenesis. J. Biol. Chem. 279:4877-4886.

Sluss, H.K., Armata, H., Gallant, J., Zhu, Z., and Jones, S.N. (2004). Phosphorylation of serine 18 regulates distinct p53 functions in mice. Mol. Cell. Biol. 24:976-984.

Steinman, H., Sluss, H.K., Pihan, G., Sands, A., and Jones, S.N. (2004). Absence of p21 partially rescues Mdm4 loss and uncovers an anti-proliferative effect of Mdm4 on cell growth. Oncogene 23:303-306.

Rogoff, H., Pickering, M.T., Frame, F., Sanchez, Y., Jones, S., and Kowalik, T. (2004). Apoptosis associated with deregulated E2F activity is dependent on E2F1 and ATM/Nbs1/Chk2. Mol. Cell Biol. 24:2968-2977.

Cha, K., Douglas, K., Potok, M.A., Liang, H., Jones, S.N., and Camper, S. (2004). Wingless signaling affects pituitary gland shape. Mech Dev. 121:183-194.

Kennedy  , N.J., Sluss, H.K., Jones, S.N., Bar-sagi, D., Flavell, R.A., and Davis, R.J. (2003). Suppression of Ras-stimulated transformation by the JNK signal transduction pathway. Genes & Dev. 17: 629-637.

Liang, H., Chen, Q., Coles, A., Anderson  , S., Pihan, G., Gerstein, R., Jureceic, R., and Jones, S.N. (2003). Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 4:349-360.

Houghtaling, S., Timmers, C., Noll. M., Reifsteck, C., Olson, S., Finegold, M., Jones, S., Meyn, S. and Grompe, M. (2003). Epithelial cancer in Fanconi Anemia D2 (Fancd2) knockout mice. Genes & Dev. 17:2021-2035.

Tyner, S.D., Venkatachalam, S., Choi, J., Jones, S., Ghebranious, N., Igelmann, H., Lu, X., Soron, G., Cooper, B., Brayton, C., Karsenty, G., Bradley, A., and Donehower, L.A. (2002) p53 mutant mice that display early ageing-associated phenotypes. (2002). Nature 415: 45-53.

Steinman, H., and Jones, S.N. (2002). Generation of an Mdm2 conditional allele in mice. Genesis 32:142-144.

Rogoff, H.A., Pickering  , M.T., Debatis, M.E., Jones, S.N. and Kowalik, T.F. (2002). E2F1 Induces Phosphorylation of p53 that is Coincident with p53 Accumulation and Apoptosis. Mol. Cell Biol. 22:5308-5318

Tournier, C., Dong, C.,Turner, T.K., Jones, S.N., Flavell, R.A., and Davis  , R.J. (2001). MKK7 is an essential component of the JNK signal transduction pathway activated by pro-inflammatory cytokines. Genes & Dev 15:1419-1426.

Guidi, C., Turner, T., Smith, T., Zambowski, B., Sands, A.S., Imbalzano, T., and Jones, S.N. (2001). Disruption of Ini1 leads to peri-implantation lethality and tumorigenesis in mice. Mol. Cell. Biol.    21:3598-3603.

Whitmarsh, A.J., Kuan, C-Y., Kennedy, N., Kelkar, N., Yaydar, T., Mordes, J.P., Appel, M., Rossini, A., Jones, S.N., Flavell, R.A., Raskic, P., and Davis  , R.J. (2001). Co-ordination of the JNK signaling pathway by the MAPK scaffold JIP1. Genes & Dev 15:2421-2431.

Tournier, C., Hess, P., Yang, D.D., Xu, J., Turner, T.K., Nimnual, A., Bar-Sagi, D., Jones, S.N., Flavell, R.A., and Davis  , R.J. (2000). Requirement of JNK for stress induced activation of the cytochrome c-mediated death pathway. Science 288: 870-874.

Yamaguchi,T., Bradley, A., McMahon, A.E. and Jones, S. (1999).   A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo. Development 126: 1211-1223.

Jones, S.N., Hancock, A.E., Vogel, H., Donehower, L.A.  and Bradley, A. (1998). Overexpression of Mdm2 in transgenic mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc. Natl. Acad. Sci. USA. 95: 15608-15612.

Fuchs, S.Y., Adler, V., Buschmann, T., Yin, Z., Wu, X., Jones, S.N. and Ronai, Z. (1998).   JNK targets p53 ubiquitination and degradation in nonstressed cells. Genes & Dev. 12: 2658-2663.

Kubbutat, M.H.G., Jones, S.N. and Vousden, K.H. (1997).   Regulation of p53 stability by Mdm2. Nature 387: 299-303.

Jones, S.N., Sands, A., Hancock, A.E., Vogel, H., Donehower, L.A.  , Linke, S.P., Wahl, G.M. and Bradley, A. (1996).  The tumorigenic potential and cell growth characteristics of p53-deficient cells are equivalent in the presence or absence of Mdm2.  Proc. Natl. Acad. Sci. USA . 93: 14106-14111.

Jones, S.N., Roe, A.E., Donehower, L.A. and Bradley, A. (1995).  Rescue of embryonic lethality in Mdm2 deficient mice by absence of p53. Nature 378: 206-208.

Potential Rotation Projects

Project #1: Generate a conditional allele of p53 or Mdm2 using heterologous loxP sites in order to facilitate rapid swapping of specifically mutated forms of these genes with the wt copy in ES cells, and subsequently in mice.

Project #2: Generate a conditional allele of the Ini1 chromatin remodeling subunit in order to address the role of Ini1 in the development of muscle and in neural crest progenitor cells.

Academic Background

Ph.D., 1988, Vanderbilt University School of Medicine

Office: S3-123
Phone: 508-856-7500
E-mail: Stephen.Jones@umassmed.edu
Keywords: Oncogenes/tumor suppressors, Cancer, Cell Cycle, Mouse Genetics, Mouse Models

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