Pocket protein family function in mesenchymal tissue development and tumorigenesis

pRB is a member of the pocket protein family, which includes the closely related proteins p107 and p130. The pocket proteins are critical regulators of the cell cycle and function to restrain proliferation by controlling the activity of the E2F family of transcription factors. The pocket proteins also play an important role in the development of many tissues. Due to the frequency of mutation of pRB in Osteosarcoma, and its role in the development of tissues of mesenchymal origin, we sought to understand the consequence of the loss of pRb, and its family member p107, in murine mesenchymal cells. The early lethality of Rb-/- mice hampers the study of many mesenchymal tissues, thus we conditionally deleted Rb in the mesenchymal progenitors of p107 mice. These mice develop embryonic skeletal abnormalities characterized by wider and shorter long bones and malformed sternums. Analysis of the defects revealed that inappropriate proliferation of chondrocytes in the growth plate contributed to the phenotype. Mutant adult mice displayed an exacerbated cartilage and growth plate phenotypes, which corresponded to ectopically proliferating growth plate chondrocytes and altered chondrocyte differentiation. Notably, these cartilage defects were consistently associated with the development of enchondromas, a cartilage neoplasm. We also examined the role of pRb, and its cooperation with the tumor suppressor p53, in the development of murine osteosarcoma. We examined the effect of mutation of Rb and p53 in bone marrow-derived mesenchymal cells, which contains the putative cell of origin of osteosarcoma.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2009

Author dc:creator

• Landman, Allison Simone

Advisor dc:contributor.advisor

• Jacqueline A. Lees.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/54568

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/54568