The work reported here involves studies of suppressor T cells (T[sub=s]C) and their suppressor factor (SF) which specifically suppress the in vitro generation of cells cytotoxic for a syngeneic tumor, P815, in DBA/2 mice. This work can be divided into three sections: a) the immunogenetic properties and requirements of this T[sub=s]C and SF, b) the Lyt phenotype of the T[sub=s]C as well as that of the cells involved in the cytotoxic response to the syngeneic tumor, c) the properties of syngeneic and allogeneic antisera raised to the P815 specific SF. a) P815-antigen specific T[sub=s]C and suppressive extracts obtained from the thymuses of DBA/2 mice bearing small syngeneic P815 tumors, were compared for their immunogenetic properties and requirements. It was shown that pretreatment of T[sub=s]C populations with anti-la[sub=d] antiserum plus rabbit complement removed the suppressive activity. Similarly, absorption of the SF with anti-la[sup=d] antiserum removed the suppressive properties of the material. It was found that the T[sub=s]C and SF were capable of specifically suppressing the anti-P815 response of B6D2F₁ radiation chimeras possessing lymphoid cells of the H-2[sup=b] or H-2[sup=t2] haplotype equally as well as they could suppress the response of H-2[sup=d] bearing cells. This indicates that the T[sub=s]C and SF are not H-2 restricted with respect to K or D markers on responder cells in this system. b) T[sub=s]C were also identified in the spleens of DBA/2 mice injected intraperitoneally with membrane extracts of the P815 tumor. The Lyt phenotypes of various effector cells was determined. DBA/2 allogeneic killer cells were identified as Lyt-1⁺2⁺, whereas the syngeneic effector cells were found to be predominantly Lyt-1⁺2⁺. The suppressor cell population lost its ability to suppress the in vitro cytotoxic anti-P815 response after treatment with anti-Lyt-1 serum plus complement but not after treatment with anti-Lyt-2 serum, indicating that an Lyt-1⁺2⁻ cell is essential in this suppression. c) P815 tumor-specific SF was partially purified by passage of suppressive spleen extracts through an immunoadsorbent containing P815 membrane components. Antisera raised in syngeneic DBA/2 and allogeneic, C57BL/6, mice were tested. It was found that these antisera, but not their controls were capable of absorbing out the SF. The antisera were also capable, in the presence of complement, of eliminating T[sub=s]C from suppressive spleen cell populations. However, the antisera were not capable of eliminating syngeneic tumor specific in vitro generated killer cells, indicating that the receptor molecules on suppressor and effector cells in this system are distinct from each other. Only the antisera "raised in syngeneic DBA/2 mice had any observable effect on P815 tumor growth in vivo. / Science, Faculty of / Microbiology and Immunology, Department of / Graduate

>Magister Scientiae - MSc / Retinoblastoma Binding Protein 6 (RBBP6) is a 200 KDa multi-domain protein that has been shown to play a role in mRNA processing, cell cycle arrest and apoptosis. RBBP6 interacts with tumour suppressor proteins such as p53 and pRb and has been shown cooperate with Murine Double Minute 2 (MDM2) protein in catalyzing ubiquitination and suppression of p53. Unpublished data from our laboratory has suggested that RBBP6 and MDM2 interact with each other through their RING finger domains. RBBP6 has also been shown to have its own E3 ubiquitin ligase activity, catalyzing ubiquitination of Y-Box Binding Protein 1 (YB-1) in vitro and in vivo. YB- 1 is a multifunctional oncogenic protein that is generally associated with poor prognosis in cancer, tumourigenesis, metastasis and chemotherapeutic resistance. Unpublished data from our laboratory shows that RBBP6 catalyzes poly-ubiquitination of YB-1, using Ubiquitin-conjugating enzyme H1 (UbcH1) as E2 ubiquitin conjugating enzyme. We have furthermore shown that the zinc knuckle of RBBP6 interacts specifically with the Ubiquitin-associated domain (UBA) domain of UbcH1.

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

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