TitleThe role of Pak4 in tumorigenesis in vivo
NameLiu, Yingying (author), Minden, Audrey (chair), yang, chung s (internal member), Conney, Allan H (internal member), Zhou, Renping (internal member), Chen, Suzie (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectPharmacology, Cellular and Molecular,
DescriptionThe Pak4 (P21 activated kinase) serine/threonine kinase is an important effector of Rho GTPases and has been implicated in the regulation of cell morphology and motility, as well as cell growth control. Our preliminary data showed that both Pak4 mRNA and protein are highly expressed in primary tumors and almost every tumor cell line, while there is a very low expression level in normal tissues. The goal of this thesis was to study the role of Pak4 in tumorigenesis. First, I investigated whether overexpression of Pak4 is sufficient to induce tumor formation. Fibroblast cell line NIH3T3 and immortalized mouse mammary epithelial cells (iMMECs) transfected with Pak4 were used. We found that overexpression of Pak4 in both cell lines led to formation of tumors in athymic mice. Furthermore, overexpression of Pak4 in iMMECs led to changes in 3D acinar architecture, including decreased central acinar cell death, abrogation of lumen formation, and cell polarity alteration. The results suggest that Pak4 can promote cell survival and proliferation, as well as alter cell shape and polarity, as part of the oncogenic process. Next, I investigated whether Pak4 is necessary for tumorigenesis in response to oncogenes such as Ras and Cdc42. Pak4 conventional knockout 3T3 cell lines and Pak4 conditional knockout 3T3 cell lines transfected with Ras or Cdc42 were used. We found that in cells transfected with oncogenic Ras, tumors grew more slowly and to a smaller size when Pak4 was deleted. In cells transfected with Cdc42, tumor formation was almost completely abrogated when Pak4 was absent. These results would be consistent with the role for Pak4 as a Cdc42 effector protein involved in signaling pathways leading from Cdc42 and its activators to transformation, and its critical role in cell survival and inhibition of apoptosis. This work shows for the first time that overexpression of Pak4 in epithelial cells leads to tumorigenesis in vivo, and that Pak4 is necessary for tumorigenesis in response to certain oncogenes. These findings make Pak4 an attractive target for cancer prevention or therapy.
NoteIncludes bibliographical references
Noteby Yingying Liu
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.