PubMed · 17184667
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Thomas D'Amico. 2007. Invited commentary.. https://doi.org/10.1016/j.athoracsur.2006.10.025
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Recent results suggest a role for topoIIalpha (topoisomerase IIalpha) in the fine-tuning of mitotic entry. Mitotic entry is accompanied by the formation of specific phosphoepitopes such as MPM-2 (mitotic protein monoclonal 2) that are believed to control mitotic processes. Surprisingly, the MPM-2 kinase of topoIIalpha was identified as protein kinase CK2, otherwise known as a constitutive interphase kinase. This suggested the existence of alternative pathways for the creation of mitotic phosphoepitopes, different from the classical pathway where the substrate is phosphorylated by a mitotic kinase. In the present paper, we report that topoIIalpha is co-localized with both CK2 and PP2A (protein phosphatase 2A) during interphase. Simultaneous incubation of purified topoIIalpha with CK2 and PP2A had minimal influence on the total phosphorylation levels of topoIIalpha, but resulted in complete disappearance of the MPM-2 phosphoepitope owing to opposite sequence preferences of CK2 and PP2A. Accordingly, short-term exposure of interphase cells to okadaic acid, a selective PP2A inhibitor, was accompanied by the specific appearance of the MPM-2 phosphoepitope on topoIIalpha. During early mitosis, PP2A was translocated from the nucleus, while CK2 remained in the nucleus until pro-metaphase thus permitting the formation of the MPM-2 phosphoepitope. These results underline the importance of protein phosphatases as an alternative way of creating cell-cycle-specific phosphoepitopes.
To improve tumor targeting in a subset of patients, where tumor cells do not express the well-known tumor antigens widely used in immunotherapy, we have developed a novel biotechnological tool. It is useful for tumors of various origins for the identification of tumor-associated proteins, which are differentially expressed in tumor cells with respect to normal tissue, and exposed on the cell surface. For this purpose, a combination of techniques, such as "suppression subtractive hybridization" and "transmembrane trapping," was employed. In applying this novel approach to breast cancer, we identified a large panel of cDNA fragments encoding for the well-known tumor-associated surface antigens, such as erb-B2, erbB3 and the urokinase receptor and, more importantly, for several clones overexpressed in breast cancer, whose cDNA fragments match the sequences of hypothetical transmembrane proteins with unknown function. The latter may represent novel tumor-specific targets.
The expression of the melanoma-associated antigen (MAGE) genes consists of variables in all tumor types, such as lung cancer, which are relevant to be silent in all normal tissues except germ cells. They are considered as tumor-specific antigens, and are ideal targets for cancer immunotherapy. A complete MAGE genes differential expression profile analysis of lung cancer can provide this study not only various target genes for immunotherapy, but also valuable markers for further diagnosis and prognosis. This research has constructed a membrane array, which was consisted 32 MAGE genes, to detect whether the differential expression profile occurred in 52 pairs of non-small-cell lung cancer (NSCLC) samples. Nearly 32 MAGE genes have been differential expressed in NSCLC except MAGE-B1 and -E2. MAGE-B, -C, -D, and subgroup -B6, -D4 have showed prominences in lung adenocarcinoma. High-frequent expression of MAGE-D, and subgroup -A2, -D2 has also been discovered in non-metastasis group (p<0.05). However, there is no significant difference of MAGE genes differential expression shown among different primary tumor (T), nodal involvement (N) and overall stages. Several MAGE subgroup genes, such as MAGE-A5, -A7, -A8, -A9, -A11, -B3, -B4, -B10, -D2, -D3, -F1, -G1, -H1, and -L2, have been first discovered to show differential expression in NSCLC. Although the small size of the sample may limit the diagnostic and prognostic value of MAGE genes, the function of the membrane array can provide this study a high-throughput method to detect the whole MAGE genes differential expression profile.