PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers (1,2). Germ line mutations of PTEN are also the cause of PTEN hamartoma tumor syndromes (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, Proteus-like syndrome) with increased risk for the development of cancers (3). Cowden syndrome is a rare, autosomal dominant, familial cancer syndrome characterised by hamartomas, acral keratosis, multiple smooth facial papules, and multiple oral papillomas (4). In contrast, Bannayan-Riley-Ruvalcaba syndrome is characterized by lipomatosis, macrocephaly, hemangiomatosis (5). Loss of heterozygosity (LOH) studies suggest that PTEN may play its most important role in advanced cancers of particular tissue (6). Alterations of PTEN in tumors are associated with a poor prognosis (7). Germinal mutations of the p53 gene constitute an etiological genetic base of Li-Fraumeni syndrome, which is a rare genetically and clinically heterogeneous autosomal dominant inherited cancer disorder, characterized by a specific range of tumors observed at an early age, in particular a predominance of bone and soft tissue sarcomas and breast cancer (8). Generally, cells with dysfunctional p53 are predisposed to development of cancer phenotype. Of importance, it is mutated frequently in the common human malignancies of the breast and colon rectum and also in other significant cancers such as glioblastoma with less frequency (9).

The PTEN and p53 tumor suppressors are among the most commonly inactivated or mutated genes in human cancer (10). The PTEN has been shown to be involved in a complex network of interactions with p53 (Fig. 1). Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription. Once PTEN is lost, however, the p53 pathway is strongly activated (11,12). Furthermore, an absence of PTEN cooperates with an absence of p53 to promote cancer (13). The inactivation of tumor suppression may be caused by lack of key interaction partners. Recent studies have revealed a functional ubiquitin ligase for tumor suppressors playing a pivotal role in tumor cell survival (14,15). Mutations found in genes such as p53 and PTEN have emerged as high penetrance susceptibility genes and are clinically relevant for determination of cancer risk. In this review, we summarize the current research and our view of how and when PTEN and p53 with their partners transduce signals downstream and the implications for cancer-associated biology.

The human genomic PTEN locus consists of 9 exons on chromosome 10q23.3 encoding a 5.5 kb mRNA that specifies a 403 amino acid open reading frame (16,17). The translation product is a 53 kDa protein with homology to tensin and protein tyrosine phosphatases. PTEN is ubiquitously expressed throughout early embryogenesis in mammals (18). PTEN gene can be upregulated by early growth regulated transcription factor 1, peroxisome proliferator activated receptor γ (PPARγ), p53, and activating transcription factor 2 (ATF2) (19–22), while transforming growth factor (TGF)-β, nuclear factor κB (NF-κB), and Jun negatively regulate PTEN expression (23–25). Of note, rosemary extract represses PTEN expression in K562 leukemic culture cells (26). PTEN activity can be regulated by posttranslational regulation including phosphorylation, acetylation, and oxidation. Methylation of the PTEN promoter can result in transcriptional silencing of the PTEN gene (27). Schematic structure of the predicted PTEN protein is shown in Fig. 2. PTEN negatively regulates the activity of PI3K/AKT signaling through converting phosphatidylinositol 3,4,5-triphosphate (PIP3) into phosphatidylinositol 4,5- bisphosphate (PIP2). The PIP3 is the principal second messenger of the PI3K pathway that mediates receptor tyrosine kinase (RTK) signaling to the survival kinase AKT. Activated AKT transfers a phosphate group to target proteins involved in cell survival, cell cycling, proliferation, and migration, which also are all critical for tumor development (28,29).

PTEN acts as regulator of maintaining basal levels of PIP3 below a threshold for the signaling activation. PTEN protein consists of N-terminal phosphatase, and C-terminal C2, and PDZ (PSD-95, DLG1, and ZO-1) binding domains. The PTEN CX5R(S/T) motif resides within an active site that surrounds the catalytic signature with three basic residues, which are critical for PTEN lipid phosphatase activity. The structure endows PTEN with its preference for acidic phospholipid substrates such as PIP3. Overexpression of PTEN induces growth suppression by promoting cell cycle arrest, which requires lipid phosphatase activity (30,31). Overexpression of PTEN also correlates with decreased levels and nuclear localization of cyclin D1 (32), a key cell cycle molecule regulated by AKT. One mechanism by which PTEN induces cell cycle arrest is the regulation of AKT activity such that levels of the cell cycle inhibitor p27kip1 are increased (33). However, despite the main role of PTEN as a negative regulator of the PI3K pathway, studies report various tumor suppressive activities for PTEN that are exerted from within the nucleus, where catalysis of PIP3 does not seem to represent a dominant function of this enzyme (34). The nuclear PTEN activities may include the regulation of genomic stability, cell cycle progression, and gene expression.

The p53 gene, located on chromosome 17p 13.1 and encoding a nuclear 393-amino acid protein, acts to control cell growth and apoptosis (Fig. 2). The p53 protein is a transcription factor which is able to induce G1 arrest of the cell cycle by transactivating several downstream genes. Inactivation of p53 gene is a common event in the development of most types of cancer. The importance of p53 as an inherited cancer susceptibility gene has been demonstrated in Li-Fraumeni syndrome (35). However, there are still a significant number of Li-Fraumeni families for which no underlying genetic determinant has been identified. It would be beneficial to understand the alterations of genes or additional components involved in DNA damage recognition, DNA repair, and/or cell cycle checkpoint pathways responsible for the specific phenotype.

PTEN and p53 is known to interact and regulate each other at the transcription as well as protein level, which could be at the important control machinery for switching between survival and death. This cross talk is frequently a combination of reciprocally antagonistic pathways, which often involves another tumor suppressor gene MDM2, and may serve as an added regulatory effect on the expression of key genes involved in cancer. It has also been revealed that PTEN regulates p53 stability and in turn regulates its own transcriptional activity.

The PTEN gene is found in 80% of Cowden syndrome patients (63,64). Mutations of the PTEN gene are thus frequent in hereditary cancer syndromes, and are found in all exons except 1, 4, and 9 in Cowden syndrome (63–65). These mutations target the PTEN gene not only at its coding regions, but also at exon-intron boundaries and promoter regions, most of which have a major impact in the PTEN protein levels of expression, being causative of PTEN functional deficiency and considered as pathogenic (66,67). It has been suggested that the differential expression of the PTEN gene correlates with the different phenotypes. Mutations targeting the PTEN coding region include frame-shift and nonsense mutations, which also generate unstable truncated PTEN proteins, as well as missense mutations that result in individual amino acid changes. Functional analyses of these missense mutations have revealed that the amino acid substitutions generate PTEN proteins with impaired intrinsic catalytic activity and/or protein stability (68–70).

Some examples have been described of missense PTEN mutations that do not affect the intrinsic catalysis nor the stability of the protein, but rather impair essential regulatory PTEN properties, such as binding to membranes or nuclear entry (71). PTEN hamartoma tumor syndrome is the term used to describe Cowden syndrome (65). Mutations in PTEN together with p53 make the tumor suppressor genes one of the most frequently affected in human malignancies in solid tumors (72–74). PTEN is considered haplo-insufficient to prevent certain malignancies, suggesting that dosage is important for its function, as it is influenced by a given point mutation in the catalytic activity of the enzyme (75). Tumors initiated by a subtle downregulation of a tumor suppressor gene can progress in the absence of LOH of the wild-type allele (76). These regulatory cues are presumed to play a key role in tumorigenesis through the alteration of the appropriate levels, localization, and activity of PTEN. However, it has been shown that PTEN germ-line SNPs are unlikely to have an important role in hereditary prostate susceptibility (77). The lifetime risk of breast cancer for Cowden syndrome patients is 81% (78), and bilateral risk-reducing mastectomy with immediate reconstruction is performed to eliminate further risk of breast cancer (79).

Advances in the field of hereditary cancer genetics have led to an improved understanding of detection and prevention strategies. Germline genetic testing for mutations in PTEN and p53 allows for the identification of individuals at increased risk for breast, ovarian and other cancers. PTEN and p53 may be regulated and interact with each other at multiple levels including transcription, protein modulation, and protein stability (80,81). Understanding the regulation is crucial for the effective design of novel cancer therapeutics. In addition, it is important to investigate the functional linkage between PTEN, p53 and MDM2 isoforms in human cancer samples, and elucidation of interaction-specific functions may provide insight into regulatory aspects of these tumor suppressors as well as opportunities for therapeutic intervention. Further mechanistic studies are needed in order to understand the precise molecular mechanisms for the effective treatment of both cancer and other diseases with their alteration.