Pocket Protein Family Function in Mesenchymal Tissue Development and Tumorigenesis

Links

URL: https://dspace.mit.edu/handle/1721.1/54568

Abstract

RB 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. 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.

Cited Works (12)

Year	Entry
2002	Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. April 2002;2(4):389-406.
2002	Akiyama H, Chaboissier M-C, Martin JF, Schedl A, de Crombrugghe B. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. November 1, 2002;16(21):2813-2828.
1997	Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsent G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. May 30, 1997;89(5):747-754.
2003	Kronenberg HM. Developmental regulation of the growth plate. Nature. May 15, 2003;423(6937):332-336.
1999	Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. May 1999;22(1):85-89.
1999	St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. August 15, 1999;13(16):2072-2086.
1997	Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. May 30, 1997;89(5):765-771.
2006	Rodda SJ, McMahon AP. Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. August 15, 2006;133(16):3231-3244.
2002	Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. January 11, 2002;108(1):17-29.
1997	Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao Y-H, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. May 30, 1997;89(5):755-764.
2007	Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age‐related changes in trabecular architecture differ in female and male C57BL/6J mice. J Bone Miner Res. August 2007;22(8):1197-1207.
2003	Harada S-i, Rodan GA. Control of osteoblast function and regulation of bone mass. Nature. May 15, 2003;423(6937):349-355.