The tumour suppressor gene p53 is pivotal in the regulation of program cell death (apoptosis), and point mutations within the gene represent the most common genetic alterations in human cancers. This process can result in the overexpression and/or accumulation of mutated and/or wild-type p53 protein within the cell. Cytotoxic T lymphocytes (CTL) play a critical role in the immune defense by recognising peptide/MHC complexes on the surface of virally infected or tumour cells followed by lysis. Therefore, p53-derived peptides are potential candidates for immunisation strategies designed to induce anti-tumour CTL in patients.

Bcl10 is one of the apoptosis regulatory protein. It is located at 1p22,one site harbor tumor suppressor tumor gene. We screen Bcl10 expression in different tumor cell lines by reverse transcription-polymerase chain reaction(RT-PCR), western blot(WB) and immunohistochemistry(IHC). The results showed Bcl10 genomic expression was found in U87, Astrocytoma and no expression in glioma , glioblastoma. There were cell lines with expressions in Bcl10 protein and NF-£eB including hepatocellular carcinoma, glioblastoma, and breast cancer, but increased in lung cancer cell line. In immunohistochemistry,we found the Bcl10 protein has positive finding in glioma U373, U251; oral cancer CA922, SAS, clinical patient VGH283; Lung cancer PC14, PC13; Hepatoma Huh7; Colon cancer SW 480; Cervical cancer HeLa. The Bcl10 gene, unlike other tumor suppressor genes such as p53, may be selectively targeted by different human tumors. In our study, Bcl10 play a role in brain tumor, oral cancer and some tumor cell line had not been reported before.

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).

MOB (Mps One Binder) is a conserved gene family found in all major kingdoms. The MOB genes are essential components acting in mitotic exit and cytokinesis in both budding and fission yeasts. They are further identified as tumor suppressors in Drosophila (D.) melanogaster. Recently, they are found to be involved in the emerging Drosophila Hippo-LATS tumor suppressor pathway. Seven human homologs of yeast MOB (hMOB1A, 1B, 2A, 2B, 3, 4, 5) have been discovered. The hMOB1B is the gene that has been extensively studied and is reported to be required for the activation of LATS (Large Tumor Suppressor)/NDR (Nuclear Dbf2-related) protein kinase family, however, the functional significance of the gene remains unknown. This study is the first to elucidate the biological and biochemical functions of all seven human MOBs. By examining hMOB mRNA expression in various human tissues, we found that the hMOBs have exhibited different expression patterns. We also investigated the subcellular localization of hMOBs during interphase through immunofluorescent analysis. While hMOB2A is localized in the cytoplasm, hMOB4 is exclusively found in the nucleus. All of the other hMOBs are localized in both cytoplasm and nucleus. Furthermore, we identified hMOB1A and hMOB1B as the main binding partners of LATS and NDR in vitro. Additionally, we successfully identified a region on hMOB1B for the interaction with LATS or NDR and determined the crucial residue that is responsible for the binding of LATS2 with hMOB1B. Most significantly, we found that over-expression of hMOB1B in human cancer cells inhibits cell proliferation and induces cell death. Moreover, hMOB1B when targeted to the plasma membrane dramatically enhances the phenotype. Conversely, small interfering (si) RNA-mediated suppression of either endogenous hMOB1A or hMOB1B causes increased cell proliferation, whereas suppression of both hMOB1A and hMOB1B demonstrates a more significant enhancement in tumor cell growth. Moreover, co-expression of both LATS and hMOB1B targeted to the plasma membrane completely abolishes cell proliferation. Our findings provide convincing evidence that hMOB1A and hMOB1B function as negative regulators of cell proliferation and as pro-apoptotic proteins. Understanding hMOBs functions in the cell and their possible role in tumorigenesis can provide important information for the diagnosis and treatment of human cancers. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-09-23 14:18:43.896

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p53 is a tumour suppressor protein that is stabilised and activated by DNA damage. DNA damage-induced p53 is able to bring about either cell cycle arrest or apoptosis by the induction of p53-responsive genes such as mdm2 and p21 waf-I. Mdm2 regulates p53 function by blocking the transcriptional transactivation domain of p53 and also by targeting p53 for degradation via an ubiquitin-mediated pathway. Increases in the levels and activity of p53 are brought about by post-translational modifications. The most widely studied modification of p53 is phosphorylation, mediated by several DNA damageactivated kinases. Poly(ADP-Ribose) Polymerase-l (PARP-l) is also a DNA damageactivated enzyme which covalently modifies several target proteins by poly(ADPribosylation). It is well established that PARP-1 plays a key role in DNA base excision repair. More recently, several studies have implicated PARP-1 in the regulation of p53 function in response to DNA damage, although the nature of this relationship has been controversial. This study aimed to clarify and investigate further the role of PARP-1 in p53 regulation using PARP-1 proficient and PARP-1 deficient mouse embryonic fibroblasts (MEFs) as well as a novel potent PARP-1 inhibitor (AGI4361; Ki < 6nM). In this study, both primary and immortalised PARP-l MEFs were used. Initial experiments revealed a tendency for PARP-l +/+ MEFs to develop p53 mutations during immortalisation. Interestingly. PARP-1 -/- MEFs retained wild-type p53, suggesting that the absence of PARP-l bypasses the requirement for p53 to be mutated during the immortalisation of MEFs. As these cells could not be used to analyse p53 responses, experiments were perfonned on primary PARP-l MEFs. However. the primary PARP-l- - MEFs were found to grow very slowly compared to their PARP-1 proficient counterparts. Interestingly. treatment of primary PARP-1+1+ MEFs with AG14361 had a similar effect on cellular growth. This growth inhibition in the absence of PARP-1 was only evident in primary and not immortalised cells. It was therefore decided to stably transfect immortalised PARP-l-- MEFs, expressing wild-type p53, with a plasmid construct containing PARP-l to produce an isogenic cell line pair. These cells have been used, together with a human colorectal carcinoma cell line (HCT-116) and the potent PARP-1 inhibitor AG14361 to analyse the p53 response to different DNA damaging agents. In response to ionising radiation and ultra violet radiation, the absence of PARP-1 did not alter the induction or activity of p53. In response to the alkylating agent temozolomide, treatment of PARP-l proficient MEFs with AG14361 potentiated the increase in p53 protein levels without affecting the transcriptional transactivation activity of p53, possibly due to an impaired repair of the DNA damage and hence increased signalling to p53 due to the persistence of DNA strand breaks. However, similar results were not obtained in the absence of PARP-1 protein (P ARP-1-/- MEFs) or in HCT -116 cells treated with AG 14361 The data presented do not support the hypothesis that PARP-1 is directly involved in the DNA damage induced regulation of p53. There may, however, be an altered p53 response in the absence of PARP-l when cells are treated with particular DNA damaging agents, due to an impaired DNA repair pathway.

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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.)

No description available.