Thesis (Ph.D.)--Kent State University, 2008. / Title from PDF t.p. (viewed Jan. 26, 2010). Advisor: Bansidhar Datta. Keywords: p67, ERK1, ERK2, oncogenic KRasV12, tumor suppressor. Includes bibliographical references (p. 143-160).

Thesis (M.S.)--Marshall University, 2008. / Title from document title page. Includes abstract. Document formatted into pages: contains vi, 69 p. : ill. Includes bibliographical references (p. 59-65).

Thesis (M.S.)--Marshall University, 2008. / Title from document title page. Includes abstract. Document formatted into pages: contains 59 p. Includes bibliographical references (p. 55-59.)

Deletion on the short arm of chromosome 3 is one of the most important genetic abnormalities in the tumorigenesis of nasopharyngeal carcinoma (NPC). Both physical mapping and functional studies have targeted an NPC-related tumor suppressor gene(s) to chromosome 3p21.3. Our group has previously reported that the Ras Association Domain Family 1A (RASSF1A) gene, located within a 120-kb minimal deleted region on 3p21.3, was frequently inactivated by promoter hypermethylation in NPC. These findings suggest that RASSF1A may be a critical tumor suppressor gene in NPC. In this study, the functions of RASSF1A in NPC was characterized with the following specific aims: (1) the role of RASSF1A as a tumor suppressor in NPC cells; (2) the identification of novel RASSF1A-modulated genes and pathways in NPC; (3) the effect of RASSF1A knockdown in immortalized nasopharyngeal epithelial cells; (4) the aberrant transcription and epigenetic changes of other RASSF family of genes ( RASSFS/NORE1 and RASSF4/AD037) in NPC. / In summary, RASSF1A is a major tumor suppressor gene from 3p21.3 in NPC. RASSF1A may exert its tumor suppressor function through various biochemical pathways. The novel findings from this study revealed the role of RASSF1A in the tumorigenesis of NPC. It also led to the better understanding of the molecular pathogenesis of this endemic cancer. (Abstract shortened by UMI.) / RASSF1A is a member of the RASSF family of proteins characterized by a consensus Ras-association domain at the C-terminus. The expression and methylation status of two other members of RASSF gene family, RASSF4/AD037 and RASSF5/NORE1, were investigated in NPC. The study showed that RASSF1A, but not other members of the RASSF family, is the target tumor suppressor in this particular cancer type. / Restoration of wild-type RASSF1A, by means of transfection, in a RASSF1A-deficient NPC cell line (C666-1) led to marked growth inhibition in the NPC cells. Isolated stable clones expressing RASSF1A demonstrated retarded cell proliferation in vitro . Soft-agar assay showed decreased number and sizes of colonies formed by these clones. The expression of RASSF1A in NPC cells also led to a dramatic reduction in tumorigenic potential in nude mice. The findings provide functional evidence that RASSF1A is a target tumor suppressor gene on 3p21.3 in NPC. / Chow Shuk Nga Lillian. / "May 2005." / Adviser: Kwok Wai Lo. / Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3588. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 112-124). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

NK cell lymphoma is one of the cellular malignancies that arise from lymphocytes. Due to its rarity and aggressiveness the detailed molecular pathogenesis of NK cell lymphoma remains to be discovered. There are recent studies showing that the master regulator of B-cell differentiation into plasma cells, the Positive Regulatory Domain containing 1, with ZNF domain(PRDM1) has tumor suppressive function not only in diffuse large B-cell lymphoma (DLBCL), but also in NK cell lymphoma. The PRDM1 has two isoforms, αand β, where the former one is a functional isoform and the latter is a defective isoform with shortened and disrupted positive regulatory domain formed from transcription of internal promoter. By semi -quantitative RT-PCR, PRDM1-αexpression was found to be absent in 80% (4/5) NK cell lines while present in the normal NK cells. Loss of PRDM1 expression suggests its role as tumor suppressor. In order to study the tumor suppressive role of the αisoform of PRDM1, short-hairpin RNA (shRNA) with isoform specific sequence is used to knockdown the expression of PRDM1-αin NK cell lines. Western blot result showed about 40% decrease of PRDM1-αprotein after knockdown. Retroviral infection of the NK cell lines, NKYS and YT which have endogenous α-isoforms of expression, for the delivery of the shRNA was done and were subsequently subjected to in vitro functional analyses including MTS assay, colony formation assay, cell viability test and cell cycle analysis to determine potential effect of the loss of PRDM1-αon the NK cell lines. The PRDM1-αprotein isoform is expected to be able to repress excessive growth of NK cell line. When this isoform is inactivated, the NK cell lines are expected to proliferate significantly than the negative control counterpart in functional analyses. However in this study only YTcell line showed significant proliferation advantage in MTS and colony formation assay after the knockdown of PRDM1-α by shRNA. Cell viability assays and cell cycle analyses failed to show significant changes in both NK cell lines and yet even showed inhibitory effect after the knockdown of the gene. Ectopic expression of PRDM1-αby retroviral infection was done in KHYG cell line to further evaluate its tumor suppressive function. Apoptotic assay on the KHYG cells with ectopic expression of PRDM1-αwas performed and percentage of cells with late apoptosis was found to be significantly higher in this cell line. This suggests that one of the mechanisms for PRDM1-αto act as tumor suppressor is via the apoptosis pathway which in turn promotes the cell death. Future studies will be made to further investigate the effects of knockdown of PRDM-1αby designing another shRNA sequence which knockdown the expression of gene by at least 50% and to further investigate the role of PRDM1-αinthe pathogenesis NK cell lymphomaby proliferation assays, colony formation assay and cell cycle analysis. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Thesis (M. Phil.)--University of Hong Kong, 2007. / Also available in print.

Thesis (Ph.D.)--Georgetown University, 2008. / Includes bibliographical references.

Thesis (M.Med.Sc.)--University of Hong Kong, 2003. / Includes bibliographical references (leaves 56-60). Also available in print.

The p53 family of transcription factors, which comprises the products of the TP53, TP63 and TP73 genes, is at the hub of different signalling pathways that determine the fate of a cell. In vitro, the p53 family posses a tumour suppressive function. However, in vivo, although p53-deficient mice develop spontaneous tumours, p73 and p63 KO animals show defects in neuronal and epidermal development, respectively. The ASPP family of proteins also consists of three members: ASPP 1, ASPP2 and iASPP. They are evolutionarily conserved binding partners and specific regulators of p53-, p63- and p73- mediated apoptosis in vitro. In contrast to ASPPl and ASPP2, the biological significance of iASPP in vivo and the possible interaction with p53 family members remains unclear, and it is the subject of this study. To investigate the role of iASPP in vivo, a transgenic mouse model was generated in which iASPP expression is controlled by the Cre/loxP recombination system. Deletion of iASPP resulted in the development of a cardiocutaneous disorder which displayed features of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), defects in hair follicle position and impaired epithelial stratification. iASPP loss resulted in a sudden, premature and arrhythmic mode of death of all iASPP mutant mice. iASPP deficiency induced p53-dependent apoptosis in embryonic hearts and dilation of the right ventricle, however, the inactivation of p53 alleles only rescued the fibro-fatty deposits present in iASPP KO hearts. Mechanistically, iASPP locates at the polar ends of cardiomyocytes where it matches the location of other proteins known to be involved in the etiology of ARVC and in maintaining the integrity of intercalated discs. Loss of iASPP also resulted in increased differentiation of primary keratinocytes both in vitro and in vivo. Consistent with this, iASPP bound p63 and inhibited the transcriptional activity of both T Ap63a and T Ap63α and ΔNp63 in vitro, and regulated the expression level ofp63-regulated genes such as envoplakin. These results demonstrate that iASPP prevents cardiocutaneous disorder through its ability to inhibit p53-induced apoptosis and to influence the integrity of intercalated disc. Moreover, iASPP is also an important regulator of p63 and is involved in controlling epithelial stratification in vivo.