The p63 gene encodes at least six different proteins with homology to the tumour suppressor protein p53 and the related p53 family member p73. So far, there have been limited data concerning the expression patterns of individual p63 proteins, due to a lack of reagents that distinguish between the different isoforms. Three antibodies have been produced specifically directed against the two N-terminal isoforms (TAp63 and DeltaNp63) and the C-terminal region of the p63alpha proteins. TAp63 proteins are located suprabasally in stratified epithelia compared with the N-terminal truncated forms, which are more abundantly expressed in the basal cell layer, indicating a switch in expression of p63 isoforms during normal cellular differentiation. Analysis of squamous cell carcinomas shows DeltaNp63alpha to be the most widely expressed isoform, compatible with a role for this protein in promoting neoplastic cell growth in these tissues. DeltaNp63 protein expression is also restricted to basal cells in breast and prostate, whilst TAp63 isoforms are more widely expressed in these tissues as well as in tumours at these sites. TAp63, but not DeltaNp63 or p63alpha, is detected in normal colon and in colon carcinoma. TAp63 proteins are also expressed in the nuclei of a sub-population of lymphoid cells and in most malignant lymphomas, whereas DeltaNp63 proteins are not expressed. Taken together, a hitherto unrecognized regulation of p63 isoform expression in vivo has been uncovered, with different p63 proteins expressed during differentiation and in different cell types. The data indicate roles for specific p63 isoforms not only in maintaining epithelial stem cell populations, but also in cellular differentiation and neoplasia.

Despite intense research, the 5-year survival rate for patients with squamous cell carcinoma of the head and neck (SCCHN) is still low. Several different factors have been studied in the search for one or more factors that give important prognostic information at the time of diagnosis. Many recent studies have focused on the TP53 tumour suppressor gene, analysing its gene status and protein status. When looking at p53 protein expression, using immunohistochemistry, no correlation to patient outcome has been seen for the whole group of SCCHN. However, a significant association between p53 expression and poor patient outcome was found when looking only at patients with laryngeal squamous cell carcinomas. Also, in oral premalignant lesions, expression of p53-positive cells in the suprabasal layers of the epithelium has been seen as an indication of impending malignant development. Concerning the prognostic significance of mutations in the TP53 gene, results differ. But when restricting analysis to tumours with mutations causing an obvious change in protein, TP53 mutation was found to be a strong and independent variable for prognosticating survival. This review article gives an up-to-date overview of the p53 molecule and evaluates its possible prognostic role in SCCHN. Today it is clear that the p53 pathway is very important in SCCHN biology and potentially in its treatment. The function and importance of a few other cell cycle proteins connected to p53 are also discussed.

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Oncoprotein 18 (Opl8) has been independently identified due to its increased phosphorylation in response to external signals and its up-regulated expression in acute leukemia. We have identified two serine residues of Op18 that are phosphorylated after triggering by the T cell antigen receptor. One of these residues, Ser25, was shown to be a likely substrate for the mitogen-activated protein (MAP) kinase, while the other residue, Serl6, was shown to be phosphorylated in response to increased intracellular calcium. Our previous site-mapping studies of Opl8 also revealed that basal phosphorylation of Opl8 is mainly located on Ser38, which was found to be the primary in vitro phosphorylation site of pl3'""'-precipitated cdc2 kinase activities. These findings raised the possibility that Op18 may be a substrate for both receptor-regulated calcium-induced protein kinases and the MAP kinase family, as well as being a substrate for the cell-cycle-regulated cdc2 kinase family. In the present report we have performed site-mapping studies of cell-cycle-regulated fluctuations of Opl8 phosphorylation. The results reveal that S-phase progression of a synchronised leukemic T cell line is associated with increased phosphorylation of both the Ser2.5 and Ser38 residues. Moreover, during mitosis, a burst of phosphorylation was observed and at this stage of the cell cycle a major fraction of Op18 was phosphorylated at multiple sites. Phosphorylation of Opl8 during mitosis was located primarily on Ser38 and to lesser extent on Ser25, Ser16 and at an unidentified Cterminal residue. In vitro phosphorylation experiments, employing two distinct members of the cdc2 kinase family, were consistent with involvement of both p34-cdc2 and p33-cdk2 in cell-cycleregulated phosphorylation of Ser25 and Ser38 of Opl8. Most importantly, the ratio of Ser25/Ser38 phosphorylation observed in vitro, using either p34-cdc2 or p33-cdk2, was found to be the same as the ratio observed in intact cells during all phases of the cell cycle. These findings suggest that Op18 may be a physiological substrate for several members of the cdc2 kinase family during both the S-phase and the mitotic phase of the cell cycle.Oncoprotein 18 (Op18) has been studied in various cellular systems under different names, such as p19, stathmin, Op18 and 19K [1-41. The specific function of this intracellular protein is still unknown, but since a dramatic up-regulation is evident in many neoplasms [5-71, we have adopted the designation Op18 coined by Hailat et al. [8].Many previous studies have suggested a putative role of Op18 in signal transduction and growth control. Evidence for such a role of Op18 includes: (a) phosphorylation of Op18 in response to a multitude of external signals [4, 9, lo] (b) differentiation-stage-specific regulation of Op18 expression levels [6, 11 -141, and, most importantly; (c) tion of this phosphoprotein, we have recently aimed to identify the specific phosphorylation sites and protein kinase systems involved. The approach has involved expression of spe...

Background. In squamous cell carcinoma of the head and neck (SCCHN), overexpression of the p53 protein has been found in 34‐80% of the tumors studied. No data are available regarding p53 expression versus tumor cell proliferation and prognosis for this tumor type. Methods. p53 protein levels were studied by immunohistochemical staining of 33 primary SCCHN using 3 antibodies (D07, PAb 1801, and CM1) that react with different epitopes of the p53 protein. The cellular expression of p53 was compared with in vivo incorporation of the thymidine analog iododeoxyuridine (IdUrd) and expression of proliferating cell nuclear antigen (PCNA). Results. Twenty‐one tumors (64%) had a positive nuclear staining for p53 with the monoclonal antibody D07, which reacts with a denaturation‐resistant epitope in wild‐type and mutant p53. PAb 1801 and CM1 reacted with 19 and 20 tumors, respectively, all of which were D07‐positive. No correlation was found between incorporation of IdUrd and p53 expression or between PCNA and p53 expression. The data indicate that intracellular accumulation of the p53 protein was related to tumor stage and localization of the tumor. No indication of a clinical or prognostic significance of p53 expression in SCCHN was found. Conclusions. No association between p53 deregulation and tumor cell proliferation was found.