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Role of Rb/p16 Pathway in Pulmonary Epithelial Regulation

Simpson, David S.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291148417

Abstract Details

2010, PhD, University of Cincinnati, Medicine: Pathobiology and Molecular Medicine.
The retinoblastoma (Rb)/p16 pathway is deregulated in most cancers, providing evidence that Rb and p16 are essential in suppressing cell growth. The current paradigm is that Rb and p16 function in a linear pathway, wherein p16 arrests cells by positively regulating Rb. In human cancers, inactivation of p16 occurs more frequently than Rb loss, suggesting that p16 suppresses cancer by regulating Rb as well as the related proteins p107 and p130. However, direct evidence demonstrating that p130 or p107 cooperate with Rb to suppress epithelial cancers associated with p16 loss is currently lacking. Moreover, the contributions of Rb, p107, and p130 in suppressing cell growth and tumorigenesis in the lung are undefined. In this dissertation, Rb ablation was targeted to the lung epithelium in wild type, p107, or p130 null mice to determine unique and overlapping Rb family functions critical in tumor suppression. Rb ablation during development resulted in marked epithelial hyperplasia and apoptosis at birth, demonstrating that Rb function is critical to lung epithelial cell regulation. In contrast, p107 and p130 were not required during development but had distinct functions in the Rb-deficient epithelium: p107 was required to suppress proliferation, whereas a novel proapoptotic function was identified for p130. Adult Rb-ablated lungs lacked the epithelial phenotype seen at birth and showed compensatory p107 upregulation and p16 induction in epithelial progenitor cells that share phenotypic characteristics with human lung cancer. Hence, we hypothesized that p107 and p16 upregulation represent a mechanism whereby the lung epithelium compensates for Rb loss. Combined Rb/p107-deficient lungs developed tumors morphologically mimicking human lung cancer, indicating that p107 plays a crucial role in suppressing growth and tumorigenesis in Rb deficient lungs. To test the functional significance of p16 induction, primary lung epithelial progenitor cell cultures were established from Rb ablated, combined Rb ablated/p16-/-, and control Rb/p16 proficient lungs. Rb loss resulted in increased cell growth as a result of increased cell survival over Rb proficient controls. Surprisingly, combined Rb/p16 loss resulted in decreased growth as compared to Rb ablation alone as a consequence of increased cell death and decreased proliferation, indicating that p16 induction following Rb loss enhances pulmonary progenitor cell growth. Taken together, these studies identify distinct Rb family functions critical in controlling epithelial cell growth, and provide direct evidence that p107 cooperates with Rb to protect against a common adult cancer. These data also provide evidence that p16 has Rb-independent functions critical for controlling epithelial progenitor cell growth. Since p16 maintains both Rb and p107 in a functionally active state and regulates additional Rb-independent functions, these findings provide a molecular basis for why p16 is preferentially inactivated in human cancers.
Kathryn Wikenheiser-Brokamp, MD, PhD (Committee Chair)
Jeffrey Whitsett, MD (Committee Chair)
William Sean Davidson, PhD (Committee Member)
Susanne Wells, PhD (Committee Member)
Melanie Cushion, PhD (Committee Member)
Francis McCormack, MD (Committee Member)
162 p.
Pathology
Rb; p107; p130; p16; lung cancer

Recommended Citations

Citations

  • Simpson, D. S. (2010). Role of Rb/p16 Pathway in Pulmonary Epithelial Regulation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291148417

    APA Style (7th edition)

  • Simpson, David. Role of Rb/p16 Pathway in Pulmonary Epithelial Regulation. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291148417.

    MLA Style (8th edition)

  • Simpson, David. "Role of Rb/p16 Pathway in Pulmonary Epithelial Regulation." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1291148417

    Chicago Manual of Style (17th edition)

ucin1291148417
397
© 2010, some rights reserved.Creative Commons License Role of Rb/p16 Pathway in Pulmonary Epithelial Regulation by David S. Simpson is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.