Protein phosphatase 2A complexes and human cell transformation
By: by Jason David Arroyo
Published: 2008
Language: eng
Number of pages: 179
Description: Models of human cell transformation provide a system for studying the mechanisms that are critical to cancer development. A variety of human cell types are transformed to tumorigenicity by the expression of only four genes: human telomerase, an oncogenic allele of H-Ras , and the large T (LT) and small t (ST) antigens of SV40. Studies of the contribution of ST demonstrated that disruption of specific protein phosphatase 2A (PP2A) complexes is necessary to induce transformation. In addition, mutations have been observed in PP2A subunit genes in human cancers. In this dissertation, I have studied the role of PP2A complexes that are involved tumorigenesis and determined new pathways that contribute to ST-mediated cell transformation. By purifying complexes containing the PP2A B56γ subunit, which is implicated in cell transformation, I identified liprin α1 as a novel B56γ binding partner. Unexpectedly, B56γ interacts with proteins independently of PP2A complexes. Because of the breadth of pathways regulated by PP2A, the cell transformation model was used to screen a library for kinases that could functionally replace expression of ST.

From this analysis, I determined that TSSK6 can induce cell transformation and activate Akt, while a separate cell viability screen revealed that TSSK6 is necessary for the survival of INA6 multiple myeloma cells. In addition, HIPK4, CSNK1E , and AKT1 were shown to replace ST in cooperation with an activated allele of Rac1 . The strongest support for the contribution of PP2A disruption to tumorigenesis comes from the observation of cancer-associated mutations in PP2A subunit genes. In collaborative work, we demonstrated that both PP2A Aα and Aβ function as tumor suppressor genes but act through distinct mechanisms. Haplo-insufficiency for the PP2A Aα subunit leads to specific loss of PP2A Aα-B56γ-C complexes, activates Akt, and induces cell transformation. In contrast, loss of PP2A Aβ complexes transforms cells due to the phosphorylation and activation of the small GTPase RalA. The studies presented in this dissertation further our understanding of the biology of PP2A complexes in both normal and transformed states and should contribute to improved therapeutic targeting of tumors harboring PP2A disruptions.
Notes: "April 2008."

Thesis (Ph.D., Division of Medical Sciences (Experimental Pathology))--Harvard University, 2008.

Includes bibliographical references.