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Expanding the Hippo pathway : hMOB3 modulates apoptotic MST1 signaling and supports tumor growth in glioblastoma

Tang, Fengyuan. Expanding the Hippo pathway : hMOB3 modulates apoptotic MST1 signaling and supports tumor growth in glioblastoma. 2014, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_11062

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Abstract

Protein kinases are critical players of signal transduction pathways involved in development, physiological and pathological processes. Deregulation of protein kinase signaling is found to be causal or related to varieties of human diseases, such as cancer, cardiovascular disease and diabetes. The human genome encodes 518 protein kinases. Approximately 60 out of them belong to the AGC group of Serine/Threonine protein kinases, including the ste20 like MST kinase family and NDR kinase family. Members of these families are highly conserved from yeast to men and regulate essential processes such as growth, proliferation and apoptosis. The Hippo pathway is a recently identified tumor suppressive network, where the MST-NDR family kinases form a kinase cascade regulating the downstream signaling through the effector YAP/TAZ.
In addition to signaling through the NDR family kinases, the Hippo/MST kinases also control cell apoptosis bypass these classical effectors YAP/TAZ. Despite the fact that JNK, FOXO3, H2B are well characterized downstream targets of apoptotic MST kinases, the regulatory mechanisms of apoptotic MST signaling are still largely unknown.
The human MOB family consists of six members encoded by six different genes (hMOB1A, -1B, -2, -3A, -3B and -3C). While as an activator for hMOB1A/B in MST-LATS/NDR kinase cascade, hMOB2 is a specific negative regulator of NDR kinase by competing the binding of hMOB1 to NDR kinase. Although hMOB3 family members share higher amino acid identity with hMOB1 than hMOB2, hMOB3 proteins do not interact or (de)activate NDR family kinases. Hence, the functions of hMOB3A/B/C are completely undefined.
A previous microarray study performed in the lab indicated that hMOB3 family members were deregulated in glioblastoma. In the present study, we first investigated the pathological roles of human MOB3 proteins and found that hMOB3 is highly upregulated in glioblastoma. Moreover, mRNA expression levels of hMOB3 members correlate with survival, suggesting hMOB3 members as potential prognostic markers. We extended the biochemical analysis by looking for the interaction partners of hMOB3 and demonstrated that hMOB3 binds to MST1 and inhibits the apoptotic cleavage of MST1 kinase. We further verified that hMOB3 promotes tumorigenesis of gliobalstoma cells in vivo by a U87MG derived flank model. Taken together, our results suggest that manipulate hMOB3 might represent a therapeutic strategy in malignant gliomas.
Advisors:Hemmings, Brian A.
Committee Members:Hall, Michael N. and Matthias, Patrick D.
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI > Quantitative Biology > Chromosome structure and transcriptional regulation (Giorgetti)
Item Type:Thesis
Thesis no:11062
Bibsysno:Link to catalogue
Number of Pages:105 p.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:56
Deposited On:23 Dec 2014 10:16

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