The PTEN, Mdm2, p53 tumor suppressor–oncoprotein network

doi:10.1016/S0968-0004(02)02166-7

Trends in Biochemical Sciences

Volume 27, Issue 9, 1 September 2002, Pages 462-467

https://doi.org/10.1016/S0968-0004(02)02166-7 Get rights and content

Abstract

Oncoproteins and tumor-suppressor proteins regulate cell growth and viability. Recent observations show that phosphoinositide 3-kinase (PtdIns 3-kinase)–Akt signaling promotes the phosphorylation and movement of the Mdm2 oncoprotein into the nucleus, where it downregulates the p53 tumor-suppressor protein. The PTEN tumor suppressor protein inhibits activation of Akt and this restricts Mdm2 to the cytoplasm. Restriction of Mdm2 to the cytoplasm promotes p53 function and thereby sustains the sensitivity of cancer cells to chemotherapy. p53 acutely induces Mdm2, providing damaged cells the opportunity for repair, but subsequently induces PTEN, favoring the death of mutated or irrevocably damaged cells. Thus, oncoproteins and tumor suppressor proteins are networked to promote normal cell function and eliminate mutated cells.

Section snippets

PtdIns 3-kinase–Akt signaling-the mitogen/cell survival connection

Mitogens and cytokines that function as survival as well as growth factors promote cell proliferation and viability. Binding of these factors to their receptors engages signaling cascades comprising interacting macromolecules, some of which are enzymes that produce second-messengers. Phosphatidylinositol 3-kinases (PtdIns 3-kinase) comprise a diverse family in which type 1A appears primarily responsible for conveying growth and survival signals from activated receptors [2]. PtdIns 3-kinase

The Akt–Mdm2–p53 circuit

Recent work has identified and confirmed yet another substrate for Akt, the Mdm2 oncoprotein 18., 19., 20., 21.. Akt phosphorylates serine 166 and serine 186 in the domain of Mdm2 that contains a nuclear localization motif. Phosphorylation of these amino acids is obligate for translocation of Mdm2 from the cytoplasm into the nucleus. Pharmacological inhibition of PtdIns 3-kinase activity, expression of dominant-negative forms of PtdIns 3-kinase or Akt, or mutation of the Akt phosphorylation

Tumor suppressor–oncoprotein networks

The PTEN tumor suppressor protein is a dual-specificity phosphatase [33]. PTEN dephosphorylates PtdIns(3,4,5)P₃, the second-messenger produced by PtdIns 3-kinase. PTEN mutants that retain protein tyrosine phosphatase activity but lose the ability to dephosphorylate PtdIns(3,4,5)P₃ are found in tumors, indicating that the lipid phosphatase activity of PTEN is required for its tumor suppressor activity [34]. Consistent with this conclusion, PTEN-deficient tumor cell lines and immortalized

Significance of the PTEN–Mdm2–p53 network to cancer

Amplification of PtdIns 3-kinase or Akt or mutations that activate PtdIns 3-kinase–Akt signaling are associated with oncogenic transformation and are features of ovarian, colon and pancreatic cancers 48., 49., 50.. Overexpression of the Mdm2 protein is predictive of high-grade, aggressive, metastatic malignancies refractory to chemotherapy and is most often detected in sarcomas, leukemias and malignancies of the breast and prostate [24]. The PTEN gene is mutated in 40–50% of high-grade gliomas,

Autoregulation and amplification of p53 function

Cells are frequently subjected to stresses, and this leads to stabilization and accumulation of p53 (Fig. 3a), at least in part, through inhibition of Mdm2 activity [61]. However, Mdm2 is among the early genes induced by p53. Thus, a p53–Mdm2 autoregulatory feedback loop is formed [62], and this delays the onset of p53-induced apoptosis and permits cells that are not irretrievably damaged or mutated to survive (Fig. 3b). However, how do cells and p53 respond to damage or mutations that can

Conclusions

Two important tumor suppressor proteins (PTEN and p53) are functionally related. PTEN negatively regulates the PtdIns 3-kinase–Akt–Mdm2 pathway that downregulates p53. p53 upregulates PTEN, thereby protecting itself from overly robust survival signals. These relationships illustrate how proteins that induce or suppress the function of the cell death machinery are networked.

Acknowledgements

We thank Jack Dixon for his help and encouragement.

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Trends in Biochemical Sciences

ReviewThe PTEN, Mdm2, p53 tumor suppressor–oncoprotein network

Abstract

Section snippets

PtdIns 3-kinase–Akt signaling-the mitogen/cell survival connection

The Akt–Mdm2–p53 circuit

Tumor suppressor–oncoprotein networks

Significance of the PTEN–Mdm2–p53 network to cancer

Autoregulation and amplification of p53 function

Conclusions

Acknowledgements

Cell

Trends Biochem. Sci.

J. Biol. Chem.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

Gene

FEBS Lett.

Mol. Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

Cell

Semin. Oncol.

Mol. Cell

Signaling through the lipid products of phosphoinositide-3-OH kinase

Nature

Regulation of neuronal survival by the serine–threonine protein kinase Akt

Science

Antiapoptotic signaling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt

Mol. Cell. Biol.

NF-κB activation by tumour necrosis factor requires the Akt serine- threonine kinase

Nature

Activation of phosphatidylinositol 3-kinase in response to interleukin-1 leads to phosphorylation and activation of the NF-κB p65/RelA subunit

Mol. Cell. Biol.

Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells

Nat. Cell Biol.

Regulation of cell death protease caspase-9 by phosphorylation

Science

Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta)

Science

Essential role of AKT-1/protein kinase B alpha in PTEN-controlled tumorigenesis

Mol. Cell. Biol.

Activation of Akt2 inhibits anoikis and apoptosis induced by myogenic differentiation

Cell Death Differ.

A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus

Proc. Natl. Acad. Sci. U. S. A.

HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation

Nat. Cell Biol.

Phosphorylation of HDM2 by Akt

Oncogene

Review
The PTEN, Mdm2, p53 tumor suppressor–oncoprotein network