Trends in Biochemical Sciences
ReviewThe PTEN, Mdm2, p53 tumor suppressor–oncoprotein network
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.
References (63)
Programmed cell death in animal development
Cell
(1997)- et al.
Ten years of protein kinase B signaling: a hard Akt to follow
Trends Biochem. Sci.
(2001) - et al.
Phosphoinositide 3-OH kinase (PI3K) and PKB/Akt delay the onset of p53-mediated, transcriptionally dependent apoptosis
J. Biol. Chem.
(1999) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
Cell
(1997)Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor
Cell
(1999)Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1
J. Biol. Chem.
(2000)Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice
J. Biol. Chem.
(2001)p53, the cellular gatekeeper for growth and division
Cell
(1997)MDM2–master regulator of the p53 tumor suppressor protein
Gene
(2000)Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
FEBS Lett.
(1997)
p300/MDM2 complexes participate in MDM2-mediated p53 degradation
Mol. Cell
Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN
Cell
PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway
J. Biol. Chem.
PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy
J. Biol. Chem.
RB regulates the stability and the apoptotic function of p53 via MDM2
Mol. Cell
DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
Cell
The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy
Semin. Oncol.
Regulation of PTEN transcription by p53
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
Cited by (358)
Apoptosis and autophagy-related gene transcription during ovarian follicular atresia in European hake (Merluccius merluccius)
2023, Marine Environmental ResearchCell senescence in pulmonary hypertension
2022, Cellular Senescence in DiseaseThe Biological Assessment of Shikonin and β,β-dimethylacrylshikonin Using a Cellular Myxofibrosarcoma Tumor Heterogeneity Model
2023, International Journal of Molecular Sciences