Date of Award

5-1-2015

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Davie, Judith

Abstract

TBX2, a member of the T-box family of transcription factors, plays important roles in embryonic development. Aberrant expression of TBX2 is observed in many cancers, and serves as an oncogene to maintain tumor cell proliferative and malignant properties. We found that TBX2 was expressed in both embryonic myoblasts and adult proliferative satellite cells, but was quickly down regulated during muscle differentiation in mouse models, which suggests an important function of TBX2 in the early myogenesis. Using molecular and cellular biology approaches we showed that TBX2 forms complex with myogenin and MyoD, and then recruits HDAC1 to muscle-specific promoters to repress the myogenin and MyoD dependent differentiation of myoblasts. In rhabdomyosarcoma (RMS), which is typically referred to as a muscle derived cancer, we found TBX2 was over expressed in both major subtypes of RMS. The deregulated TBX2 repressed the expression of cell cycle regulators, such as p21 and p14/p19, and the tumor suppressor PTEN in RMS tumor cells. Knock down of TBX2 significantly decreased the proliferation rate of RMS cells. We also found that loss of TBX2 significantly inhibited tumorigenesis of RMS cells by decreasing cell proliferation, mobility, migration, anchorage-independent growth and xenograft formation. To determine why TBX2 was deregulated in RMS cells, we performed cellular biological experiments to understand how TBX2 is regulated by cell signaling pathways and growth factors in both normal muscle myoblasts and RMS tumor cells. In normal murine myoblasts and primary murine ARMS tumor cells TBX2 was up regulated by FGF-2 treatment, but in primary murine ERMS cells TBX2 expression showed no response to FGF-2 stimulation. In human RMS cell lines a modest up regulation of TBX2 was detected by treatment of FGF-2. RMS cells constitutively express PAX3 and PAX7 which are expressed and function in myogenic precursors, but are quickly degraded in myoblasts and during myogenesis. We found that TBX2 was a downstream target of PAX3 in RMS cells, as well as the ARMS specific fusion proteins PAX3/7-FOXO1. Our novel findings on TBX2 highlight the significant roles of TBX2 in muscle development and adult muscle regeneration, where TBX2 represses MRF activities to inhibit myogenic differentiation and promote proliferation of myoblasts. Also, our work establishes essential oncogene effects of TBX2 in driving and maintaining RMS proliferation and tumorigenesis by repressing cell cycle regulatory factors, p21 and p19/p14, and tumor suppressor of PTEN. Therefore, this work provides an exciting opportunity for development of new therapeutic treatments for TBX2 driven RMS cancer.

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