A study on the biological functions of GGAP2 and its interacting proteins : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
| Published: |
[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2005]
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| Subjects: |
| Abstract: | ABSTRACT: Mutations of the APTX gene have been found to cause Ataxia Oculomotor Apraxia 1 (AOA1) resulting in severe cerebellar atrophy. The APTX gene product Aprataxin is a ubiquitously expressed nuclear protein. Although it has been found that Aprataxin interacts with the single strand DNA break repair protein (SSBR) XRCC1 in fibroblast cell lines, the molecular mechanism underlying the cerebellar pathogenesis of AOA1 cannot be fully explained by a defect in SSBR. We report that Aprataxin interacts with a GTP-binding and GTPase-activating protein, GGAP2, in the neuron. We found that Akt phosphorylates GGAP2, enabling its translocation from the cytoplasm to the nucleus to bind Apataxin. Mutations of APTX that cause AOA1 down-regulate Akt activation and its subsequent phosphorylation of GGAP2. Interestingly, GGAP2 can interact with P50 subunit of NF-KB transcription factor, and overexpression of APTX, GGAP2 and Akt synergistically activate NF-KB, while mutations of APTX abolish the effect. The AOA1-causing mutations in APTX significantly enhance Neuro-2A and PC12 cell apoptosis relative to wild type APTX. Furthermore, in vitro guanine nucleotide exchange assays indicated that APTX might be a guanine exchange factor (GEF) for GGAP2, and mutations of APTX that cause AOA1 disease dramatically decreased the GEF activity of APTX. Thus, we propose that APTX, GGAP2 and Akt exist in one protein complex, and that mutations of APTX induce neuronal apoptosis through inhibition of Akt and NF-KB pathways, possibly causing cerebellar atrophy in AOA1 patients. We used real-time PCR and immunohistochemistry to detect that expression level of GGAP2 in prostate cancer, and found that GGAP2 expression is elevated in clinical prostate cancer patients samples. To study the biological functions of GGAP2 in prostate oncogenesis and tumor progression, we examined its effects on cell growth and foci formation. The data demonstrate that GGAP2 may stimulate prostate cancer cell proliferation and malignant transformation through Akt and NF-KB pathways in an activation-dependent way. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy December 2005." Approved as to style and content by: Mingyao Liu, James Martin, Jun Qin, Bharat Aggarwal, Richard Finnell. |
| Physical Description: | viii, 67 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 61-66). |