Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

January 2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Sheila Stewart

Abstract

Our understanding of tumors as complex organs has increased our appreciation for each component of the tumor microenvironment and its respective contribution to tumorigenesis. Fibroblasts found within a tumor actively participate in the growth, progression and metastasis of cancer cells. Senescent fibroblasts, which are permanently arrested yet metabolically active, accumulate in tissue over time where they may promote the proliferation and malignant conversion of preneoplastic cells in older individuals. I have examined the relationship between senescent fibroblasts and preneoplastic keratinocytes and identified the secreted multifunctional protein osteopontin: OPN) as a critical stromal mediating factor. RNAi-directed reduction of stromal OPN leads to decreased growth of preneoplastic keratinocytes in vitro and in vivo. Furthermore, I have demonstrated the presence of senescent stroma and associated OPN expression in the early stages of a chemical carcinogenesis mouse model, suggesting that it plays a role early in tumor formation. OPN is part of a unique transcriptional profile activated upon senescence induction. Given the significance of senescent stromal-derived factors in tumorigenesis, I have investigated the regulation of OPN and other members of the senescence-associated secretory profile: SASP). I demonstrate that SASP is coordinately upregulated in response to multiple stimuli inducing senescence namely DNA damage, chromatin modulation and ectopic expression of p27, a cyclin-dependent kinase inhibitor. However, my work on the transcriptional activation of OPN reveals that SASP contains distinct subsets governed by unique transcriptional mechanisms. To this end, I demonstrate that OPN, unlike IL6 and IL8 - two well characterized SASP members - does not require the activity of ATM or NfκB for its expression in senescence. To uncover specific activators of OPN transcription, I examined OPN's promoter and I identified a fragment that is responsive in senescent fibroblasts. Furthermore, I demonstrate that OPN transcription requires chromatin modulators. Together my work presents a model where chromatin modifications in senescence play a central role in dictating transcriptional responses that ultimately impact the tumor microenvironment.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7X34VGS

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