Subcellular localisation of p53 protein

The p53 phosphoprotein is a nuclear protein. The C-terminal region of the protein contains signals for nuclear localisation (Dang and Lee, 1989; Addison et al., 1990; Shaulsky et al., 1990). Mutant proteins with deletions in the C-terminal region show cytoplasmic localisation (Sturzbecher et al, 1988). Similarly, mutations occurring in the proximity of the nuclear localisation signal domain can affect the localisation of the human p53 (Diller et al., 1990). Consistent with this, the protein can show nuclear and/or cytoplasmic localisation. Moll et al. (1992) and Stenmark-Askmalm et al (1994) found the protein in both locations. Staining for the protein can be exclusively nuclear or cytoplasmic, or a mixture of both (Faille et al., 1994). Non-Hodgkin's lymphomas show virtually exclusive (90 out of 96 samples) nuclear staining (Pezzella et al., 1993a). Its localisation in breast cancer was described as predominantly cytoplasmic (Horak et al, 1991). Both the nucleus and the cytoplasm may be stained in melanomas (Weiss et al., 1993; Parker et al., 1994a).

In the light of the interactions of p53 with cellular proteins (see page 31), it seems likely that the subcellular localisation patterns seen in tumours might be suggestive of the pathways by which wild-type and mutant proteins might be functioning. Moll et al. (1992) carried out sequence analysis of p53 cDNAs from breast cancers showing cytoplasmic staining and found wild-type alleles in six out of seven specimens. In contrast, where nuclear staining of p53 was encountered, missense and nonsense mutations were found. Furthermore, a sample of normal lactating breast tissue also showed cytoplasmic p53 staining. Cytoplasmic accumulation of p53 is encountered in non-neoplastic salivary gland but in neoplastic lesions the distribution is mainly nuclear (Li XW et al, 1995). Kastrinakis et al. (1995) found that in some hepatic metastases of colorectal carcinomas nuclear staining for p53 was seen, but not in the corresponding primary tumours. They further showed that the metastatic tumours carried point mutations of the gene but no mutations were detectable in the primary tumours. Thus, the mutant protein might tend to localise predominantly in the nucleus. Parker et al. (1994a) showed that in Bl6 murine melanoma cells up-regulation of the metastasis-associated 18A2/ mtsl gene was accompanied by a parallel increase in the detection of p53 protein, in both nuclear and cytoplasmic locations and often with marked accumulation in the submembranous regions. They suggested that the 18A2/mtsl protein, which strongly associates with cytoskeletal proteins, might be sequestering the wild-type p53 and that this could account for the cytoplasmic location of p53-

On the basis of these observations, it may be suggested that the subcellular localisation of p53 protein might yield valuable information about the pathways of p53 functioning, especially in relation to its cooperation with other cellular proteins which might be involved with or impinge upon the processes of cellular transformation. It is conceivable, therefore, that the patterns of p53 protein staining may be related to tumour development and progression. There are several indicators in this direction. Nuclear p53 staining is far more predominant in aneuploid tumours than in diploid tumours (Sun et al., 1993). In breast cancer where both nuclear and cytoplasmic staining is seen, p53 accumulation correlates strongly with DNA ploidy, among other variables (Stenmark-Askmalm et al, 1994). There are also indications that p53 staining pattern might be related to cancer prognosis. p53 staining of both the nucleus and the cytoplasm of colorectal tumours was associated with poor survival of the patients compared with p53-negative tumours and patients with tumours that showed either nuclear or cytoplasmic staining showed intermediate survival (Sun et al, 1993). Cytoplasmic staining in the absence of nuclear staining correlated with survival free from recurrent or distant metastatic disease (Stenmark-Askmalm et al., 1994), whereas, in sharp contrast, nuclear p53 staining was found with advanced stages of prostate cancer and metastatic disease in the bone (Aprikian et al., 1994). In a series of colorectal tumours investigated by Kastrinakis et al. (1995), nuclear localisation of p53 occurred together with point mutations of the gene in hepatic metastases but not in the corresponding primary colorectal tumours. Although not every study of p53 expression contains unequivocal information about the pattern of expression, from the data available to date it would be reasonable to suggest that this would be highly relevant in the prediction of the course of the disease.

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