Electronic Thesis/Dissertation


Ionizing Radiation Regulates p21-activated Kinase Activity and Function Open Access

The p21-activated Kinase-1 (PAK-1), a member of PAK family of serine/threonine kinases, is over-expressed in human cancers. The PAK kinase family is involved in multiple physiological processes including: survival, mitosis, cell motility, transcription and translation. Growth factors such as Heregulin (HRG) stimulates PAK-1 activity and redistributes the activated PAK-1 to the leading edge of the motile cells in breast cancer cells. The physiological changes in growth factor stimulated cancer cells include alterations from globular to filamentous actin and the formation of filopodia and lamellipodia required for cell migration. Earlier data also provided compelling evidence of the involvement of PAK-1 in the cell survival via phosphatidylinositol-3 kinase (PI-3 kinase) phosphorylation dependent inactivation of pro-apoptotic protein Bcl-2-antagonist of cell death (BAD). However, it is unclear whether PAK-1 activity is affected by Ionizing Radiation (IR)-induced stress. Here, we strive to understand the dynamics of PAK-1 after gamma IR stimulation of human Hela cancer cells. Our study includes explanation of several PAK-1 dynamics after IR exposure including: elucidation of PAK-1 kinetics after Irradiation and possible multiple PAK-1 containing protein complexes. Our data suggest that PAK-1 is rapidly stimulated by IR in a cyclic manner, and exists as a major and a minor PAK-1 complex in IR-exposed cells. Two different peaks or complexes with active PAK-1 was observed. From the experiments conducted so-far, it appears that peak 1 might be the most stable form of PAK-1 complex whereas peak 2 may be transient in nature. We also found that PAK-1 interacts with two unknown IR-responsive proteins, A and B containing PAK-1 enzyme activity. Further studies are needed to understand the nature of PAK-1 bound proteins and their role in the action of PAK-1 in IR stimulated cells. Knowing that PAK-1 is activated after exposure to IR, we have yet to understand whether PAK-1 might be a component of DNA-Damage response (DDR). Once PAK-1 is activated, the ability of cancer cell to repair after radiation may be compromised and thus, inhibiting of PAK-1 may lead to a more effective treatment of breast cancer in combination with IR. Hence, the implications of this research is potentially significant in the combination cancer therapeutics.

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