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Jacqueline A. Lees. Landman, Allison Simone Massachusetts Institute of Technology. Dept. of Biology. Massachusetts Institute of Technology. Department of Biology 2010-04-28T17:02:52Z 2010-04-28T17:02:52Z 2009 2009 http://hdl.handle.net/1721.1/54568 567700639 Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2009. Vita. Cataloged from PDF version of thesis. Includes bibliographical references. 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. (cont.) We show that Rb and p53 are required for the proper differentiation of mesenchymal cells and mesenchymal cells deficient in these proteins are tumorigenic. These studies demonstrate that loss of pocket protein function in the mesenchymal lineages can be disastrous for an organism, resulting in tissue deformities and a predisposition to cancer. Thus, pocket proteins play a critical role in regulating skeletogenesis as well as in adult mesenchymal tissue homeostasis and tumor suppression. by Allison Simone Landman. Ph.D. 181 p. eng Massachusetts Institute of Technology 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. http://dspace.mit.edu/handle/1721.1/7582 Biology. Pocket protein family function in mesenchymal tissue development and tumorigenesis Thesis application/pdf false Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="30c04a1f-9fec-42ac-ab22-756fea7548ea"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>Pocket protein family function in mesenchymal tissue development and tumorigenesis</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2009</PublicationDate> <Authors> <Author> <DisplayName>Landman, Allison Simone</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Biology.</Keyword> <Abstract>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.</Abstract> <Abstract>(cont.) We show that Rb and p53 are required for the proper differentiation of mesenchymal cells and mesenchymal cells deficient in these proteins are tumorigenic. These studies demonstrate that loss of pocket protein function in the mesenchymal lineages can be disastrous for an organism, resulting in tissue deformities and a predisposition to cancer. Thus, pocket proteins play a critical role in regulating skeletogenesis as well as in adult mesenchymal tissue homeostasis and tumor suppression.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>