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Beta-catenin in liver: A matter of life and death

Nejak-Bowen, Kari Nichole (2010) Beta-catenin in liver: A matter of life and death. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Beta-catenin plays multiple roles in liver health and disease through regulation of proliferation, differentiation and metabolism. Elucidating the molecular basis of how beta-catenin regulates these diverse functions and others is the subject of this dissertation. While beta-catenin signaling undergoes temporal activation and its loss dampens liver regeneration (LR), the impact of stimulating this pathway remains unknown. We utilized transgenic (TG) mice expressing Ser45 mutated beta-catenin in hepatocytes to show a growth advantage both in vitro and during LR through cyclin-D1 regulation. Additionally, hydrodynamic delivery of Wnt-1 gene delivery induced beta-catenin activation and hepatocyte proliferation during LR. Regucalcin or senescence marker protein-30 (SMP30) was identified as a beta-catenin target in the liver through the use of hepatocyte-specific beta-catenin conditional knockout (KO) mice. SMP30 is a critical enzyme for the synthesis of ascorbic acid in murine hepatocytes, and its loss led to lower serum ascorbate levels in KO. KO hepatocytes displayed massive apoptosis in culture, which was blocked by addition of ascorbate to culture media. Additionally, apoptosis in HepG2 cells due to regucalcin knockdown was rescued by anti-oxidants. Thus, one mechanism of how beta-catenin regulates hepatocyte redox state and survival is through the control of regucalcin expression. KO livers displayed a basal increase in number of apoptotic hepatocytes. We explored the susceptibility of KO and wildtype (WT) controls to activation of the TNF-alpha mediated apoptotic pathway. Paradoxically, KO mice are refractory to D-galactosamine (GalN)/LPS, Actinomycin D (ActD)/LPS and GalN/TNF-alpha treatments showing lower morbidity than WT. NF-kappaB, a major pro-survival factor and its transcriptional targets were increased in KO basally and after injury due to lack of beta-catenin-p65 association, presence of increased basal inflammation and oxidative stress and increased TLR4 expression in KO livers. Additionally, p65 activation occurred earlier in KO than WT after LPS stimulation. Thus, paradoxical protection from TNF-alpha-mediated apoptosis in KOs occurs owing to pre-existing NF-kappaB activation that 'primes' the liver for protection against exogenous insult. Thus, we have identified beta-catenin as a pleiotropic factor regulating cell proliferation, cellular redox state and cell survival through specific genetic targets and protein-protein interactions. These findings have broad implications in acute and chronic hepatic diseases.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Nejak-Bowen, Kari Nicholeknnst5@pitt.eduKNNST5
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairStrom, Stephenstrom@pitt.eduSTROM
Committee MemberMichalopoulos, Georgemichalopoulosgk@upmc.eduMICHAL
Committee MemberSundarRaj, Nirmalasundarrajn@upmc.eduNIRMALA
Committee Member Monga, Satdarshan P.Ssmonga@pitt.eduSMONGA
Committee MemberMars, Wendywmars@pitt.eduWMARS
Committee MemberYin,
Date: 11 November 2010
Date Type: Completion
Defense Date: 6 October 2010
Approval Date: 11 November 2010
Submission Date: 30 October 2010
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: oxidative stress; partial hepatectomy; regenerative medicine; transplant therapy; wnt pathway
Other ID:, etd-10302010-134136
Date Deposited: 10 Nov 2011 20:03
Last Modified: 19 Dec 2016 14:37


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