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Title: PTEN and LKB1 regulate Cdc42 - dependent polarization and morphogenesis in colorectal epithelium
Author: Fatehullah, Aliya
ISNI:       0000 0004 2741 7930
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2012
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PTEN and LKB 1 are linked tumour suppressor genes that regulate cell polarization, a key event of tissue morphogenesis. The small Rho GTPase, Cdc42 is responsive to PTEN, LKBI and is the ultimate effector of polarized growth, mediated through the PAR6/aPKCζ polarization complex. This thesis investigates dialogue between PTEN, LKBI and Cdc42-dependent two- or three-dimensional (2D or 3D) polarized cell growth. Signalling interactions and 2D polarized growth were investigated in monolayer cultures of PTEN expressing or deficient isogenic or non-isogenic cells, complemented by studies in LKB 1 constitutively deficient LKB 1 cells. Relevant molecular pathways were investigated by transfection and/or pharmacological studies. PTEN and LKBI enhance Cdc42 activity. PTEN is a negative regulator of PI3- kinase (pI3K) signaling while LKBI activates AMPK. In separate investigations of these downstream pathways, we found that PTEN influences Cdc42 activity. We also found that aPKCζ mediated Cdc42 activation via LKB 1. Furthermore, LKB 1 - AMPK targeted therapy substantially enhanced Cdc42 activity. Both PTEN and LKB 1 enhance Cdc42-dependent 2D polarization, shown by assays of reorientation of the microtubule organizing centre (MTOC), monolayer wound assays and AMPK targeted therapy can rescue the MTOC defect of PT EN deficiency. In 3D culture, PTEN expressing Cac02 cells formed regular gland like structure with a single central lumen. Conversely, PTEN deficient Cac02 ShPTEN cultures had an abnormal multi lumen or multivacuolar phenotype that could be rescued by PTEN targeted therapy. Additionally, treatment of Caco2 ShPTEN cultures with APMK targeted therapy rescued morphogenesis, restoring a single central lumen. Taken together, these studies show dialogue between PTEN and LKB 1 pathways in regulation of cdc42-dependent polarization signaling. This principle can be exploited for rescue of defective 2D polarized growth and 3D morphogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available