Tumor Suppressor Protein PTEN Research Articles

A phase II trial of temsirolimus in metastatic neuroendocrine carcinomas (NECs)

3096 Background: NECs are a varied group of endocrine neoplasms characterized by neurosecretory granules and cell surface markers. Except for islet cell carcinomas, NECs are resistant to conventional cytotoxics. Hormonal therapy such as somatostatin analogs or local therapies such as hepatic resection or arterial embolization are generally delivered to palliate symptoms. Temsirolimus is a novel mTOR inhibitor that downregulates cascades activated by loss of the tumor suppressor protein PTEN, a defect reported in moderately differentiated NECs. Due to the lack of effective systemic therapy for NECs, loss of PTEN detected in some cases, and a report of a partial response in this tumor type from phase I trials, a multi-centre 2-stage phase II trial in NECs was conducted. Methods: Patients were eligible if they demonstrated 25% increase in tumor volume, clinical deterioration or new tumor focus in the last 6 months. Temsirolimus 25 mg was administered intravenously over 30 minutes on a weekly basis. Results: To date, 23 patients (pts) with progressive NECs have been enrolled with the following demographics from 18 pts with baseline data: median age=55, range=36–68, M:F=9:9, ECOG 0:1:2= 8:9:1, and 11 pts had prior chemotherapy. Toxicity information is available from 15 pts in 50 four weekly cycles. The most frequently encountered grade 3–4 toxicities expressed as % of treatment cycles are: hypophosphatemia (14%), hyperglycemia (10%), cough (10%), hypokalemia (8%), hypercholesterolemia (8%), and hypertension (8%). The most frequent toxicities considering all grades are: fatigue (86%), anemia (76%) and lymphopenia (70%). Among 15 pts evaluable for response thus far, 10 have achieved prolonged stable disease (range: 3–11 cycles), including 1 pt with a 24% tumor shrinkage by RECIST criteria after 4 cycles, and 2 pts who have experienced significant clinical benefit and are on cycles 9 and 11, respectively. Levels of p70S6kinase in peripheral blood mononuclear cells at 24 hours post treatment have not shown correlation with clinical outcome in the majority of pts. Markers of cell cycle inhibition and apoptosis in paired tumor biopsies will be reported. Conclusions: Temsirolimus appears to have antitumor activity in NECs, study accrual is ongoing. No significant financial relationships to disclose.

Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor

The PTEN (phosphatase and tensin homologue) tumor suppressor protein contains a single catalytic domain with both lipid and protein phosphatase activities. The remaining C-terminal half of the PTEN protein plays a role in its stability and is mutated in many clinical cancer samples. Here, we report that the PTEN C-terminal domain physically interacts with the forkhead-associated domain of the oncogenic MSP58 protein and that this interaction requires PTEN Thr-366. We further show that while MSP58 transforms Pten-/- mouse embryo fibroblasts (MEFs), concurrent introduction of wild-type PTEN causes a dramatic reduction in the number of MSP58-induced transformed foci. This PTEN-mediated inhibition of cellular transformation requires physical interaction as evidenced by the failure of PTEN(T366A) point mutation (residing within the MSP58 interaction domain) to suppress MSP-58-driven transformation. These observations, together with the capacity of catalytically inactive PTEN mutant (G129R) to suppress MSP58 oncogenicity, support the view that the C-terminal region of PTEN directly provides a previously uncharacterized biological function in its ability to regulate cellular transformation.

Dimethylsulfoxide induces upregulation of tumor suppressor protein PTEN through nuclear factor-κB activation in HL-60 cells

Dimethylsulfoxide (DMSO) has been known to differentiate HL60 cells into neutrophil like cells. Here, we provide an evidence for the involvement of tumor suppressor PTEN, an antagonist of phosphatidylinositol 3-kinase (PI3K) in the DMSO-induced differentiation of HL60 cells. DMSO upregulated PTEN with unaffecting the expression of PI3K. The upregulation of PTEN by DMSO lead to the decrease of Akt phosphorylation, a downstream of PI3K. The DMSO-induced upregulation of PTEN might be mediated by NF-κB activation, which was evidenced by the blockage of DMSO-induced PTEN upregulation with an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC).

The tumor suppressor PTEN inhibits EGF-induced TSP-1 and TIMP-1 expression in FTC-133 thyroid carcinoma cells

Thrombospondin-1 (TSP-1) is a multidomain extracellular macromolecule that was first identified as natural modulator of angiogenesis and tumor growth. In the present study, we found that epidermal growth factor (EGF) up-regulated TSP-1 expression in FTC-133 (primary tumor) but not in FTC-238 (lung metastasis) thyroid cancer cells. Both EGF and TSP-1 induced expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in a mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase (PI3-kinase)-dependent manner. In FTC-133 cells, EGF induced proliferation in a TSP-1- and TIMP-1-dependent manner. In addition, we determined that re-expression of the tumor suppressor protein PTEN induced cell death, an effect that correlated with a block of Akt kinase phosphorylation. EGF-induced TSP-1 and TIMP-1 promoter activity and protein expression were inhibited in FTC-133 cells stably expressing wtPTEN but not in cells expressing mutant PTEN. Furthermore, we found that wtPTEN inhibited EGF—but not TSP-1—stimulated FTC-133 cell migration and also inhibited invasion induced by EGF and by TSP-1. Finally, an antibody against TSP-1 reversed EGF-stimulated FTC-133 cell invasion as well as the constitutive invasive potential of FTC-238 cells. Overall, our results suggest that PTEN can function as an important modulator of extracellular matrix proteins in thyroid cancer. Therefore, analyzing differential regulation of TSP-1 by growth factors such as EGF can be helpful in understanding thyroid cancer development.

Roles of PDK-1 and PKN in regulating cell migration and cortical actin formation of PTEN-knockout cells

Mutations in the tumor suppressor protein PTEN (phosphatase and tensin homologue deleted on chromosome 10) enhance cell migration, yet the underlying molecular mechanisms remain largely uncharacterized. Loss of PTEN in mouse embryonic fibroblasts (MEFs) correlates with striking cortical actin accumulation. However, how loss of PTEN leads to cortical actin formation and whether the presence of cortical actin contributes to the increased cell migration are unclear. Here we show that overexpression of dominant-negative forms of (DN) PTEN, RhoA or its kinase-dead (KD) effector, PKN, inhibited cortical actin formation, indicating that cortical actin of Pten(-/-) MEFs is mediated by the PTEN/Rho/PKN pathway. However, neither DN RhoA nor KD PKN inhibited the enhanced migration of Pten(-/-) cells, in contrast to the inhibitory effect of DN Rac. In agreement with the previous observation that DN Akt inhibits migration of Pten(-/-) cells, we demonstrate here that overexpression of KD PDK-1, the Akt kinase, reduces Pten(-/-) cell migration. Furthermore, overexpression of DN forms of Akt, Rac, or PDK-1, all of which inhibit migration of Pten(-/-) cells, had no effect on cortical actin accumulation. Our findings suggest that PDK-1/Akt signaling pathway plays a major role in regulating cell migration induced by PTEN deficiency.

Control of tumor suppressor protein PTEN by dimethlysulfoxide in HL-60 cells

3156 Background: Dimethylsulfoxide (DMSO) has been used in the treatment of several types of cancer for several decades. However, the mechanism(s) responsible for its anti-tumoral action remains un...

Control of tumor suppressor protein PTEN by dimethlysulfoxide in HL-60 cells

3156 Background: Dimethylsulfoxide (DMSO) has been used in the treatment of several types of cancer for several decades. However, the mechanism(s) responsible for its anti-tumoral action remains unknown. A novel tumor suppressor gene, PTEN/MMAC, on chromosome 10q23 encodes a phosphatidylinositol-3'-phosphatase (PTEN) that dephosphorylates the D3 position of phosphatidylinositol-3,4,5-triphosphate (PIP3), the second messenger downstream from phosphoinositide 3-kinase (PI 3-kinase) and protein kinase B (PKB)/Akt. PKB/Akt is a Ser/Thr protein kinase implicated in mediating biological responses, including the inhibition of apoptosis and the stimulation of cell growth. The present study was designed to evaluate whether DMSO controls PTEN expression in malignant cell lines. Methods: HL-60 cells were treated with DMSO, and PTEN expression determined by western- and northern-blot analysis. NF-κB activation was measured by electrophoretic mobility shift assay. To investigate the prevention of DMSO-induced PTEN upregulation in HL-60 cells, we blocked NF-κB activity with a p65 antisense oligonucleotide and pyrrolidine dithiocarbamate (PDTC). Results: DMSO strongly induced PTEN expression through NF-κB activation in HL-60 cells. Treatment of HL-60 cells with DMSO caused significant NF-κB activation and induced an increase in PTEN expression in a time- and dose-dependent manner. Interestingly, blocking NF-κB activity prevented the DMSO-induced upregulation of PTEN, indicating that the upregulation of PTEN expression by DMSO is NF-κB-dependent. Conclusion: These results suggest that DMSO is an important stimulator of the tumor suppressor protein PTEN in leukemia cells. These studies form the basis for further investigations to improve the anti-tumor effects of DMSO against such cancers as leukemia and various kinds of solid tumors. No significant financial relationships to disclose.

Geldanamycin induces mitotic catastrophe and subsequent apoptosis in human glioma cells.

Geldanamycin (GA) binds to heat shock protein 90 (Hsp90) and interferes with its function which is to protect various cellular proteins involved in signaling, growth control, and survival from ubiquitination and subsequent degradation by the proteasome. Recently, we demonstrated that GA inhibited migration of glioma cells in vitro associated with downregulation of hypoxia-inducible factor (HIF-1 alpha) and phosphorylation of focal adhesion kinase (FAK) (Zagzag et al., 2003, J Cell Physiol 196:394-402). Here, we have investigated the mechanisms through which GA treatment of the T98G glioma cell line induces apoptosis. We found that GA treatment induced cell death in a caspase-dependent manner through activation of caspase-3 and PARP cleavage together with release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria. Use of synchronized T98G cells showed that GA treatment of glioma cells during S-phase enhanced cytotoxicity followed by M-phase arrest, resulting in mitotic catastrophe. In addition, apoptosis was associated with the downregulation of the survival protein, phosphorylated Akt (pAkt), an important signaling protein in the PI3K pathway, that is overexpressed in many cancers including gliomas. Given that many glioma tumors show deregulation of the PI3K signaling pathway, either through loss of the tumor suppressor protein PTEN or overexpression of the growth factor EGFR, the ability to identify different subsets of patients using simple immunohistochemistry for the presence of absence of pAkt could enable selection of the appropriate kinase inhibitor, such as GA, for drug therapy. Based on our data presented here, GA or its analogs may have potential in the treatment of glioma.

Tumor Suppressor Doing Double Duty

The tumor suppressor protein PTEN is a dual-specificity phosphatase whose catalytic domain acts primarily on lipids but can also target proteins. Raftopoulou et al. report that PTEN lipid phosphatase activity is not required for PTEN to inhibit cell migration. Instead, its protein phosphatase activity is required to dephosphorylate a single residue in its C-terminal tail, which in turn regulates migration. This mechanism may contribute to the progression of tumors that harbor catalytically inactive forms of PTEN. M. Raftopoulou, S. Etienne-Manneville, A. Self, S. Nicholls, A. Hall, Regulation of cell migration by the C2 domain of the tumor suppressor PTEN. Science 303 , 1179-1181 (2004). [Abstract] [Full Text]

Inhibition of phosphatidylinositol 3-kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells.

In de novo glioblastoma multiforme, loss of the tumour suppressor protein PTEN can coincide with the expression of a naturally occurring mutant epidermal growth factor receptor known as deltaEGFR. DeltaEGFR signals constitutively via the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt and mitogen-activated protein kinase pathways. In human U87MG glioblastoma cells that lack PTEN, deltaEGFR expression enhances tumourigenicity by increasing cellular proliferation. Inhibition of PI3K signaling with the pharmacologic inhibitor wortmannin, or by the reconstitution of physiological levels of PTEN to dephosphorylate the lipid products of PI3K, negated the growth advantage imparted by deltaEGFR on U87MG cells. PTEN reconstitution suppressed the elevated PI3K signaling, without affecting mitogen-activated protein kinase signaling and caused a delay in G1 cell cycle progression that was concomitant with increased cyclin-dependent protein kinase inhibitor p21CIP1/WAF1 protein levels. Our study provides insight into the mechanism by which deltaEGFR may contribute to glioblastoma development.

Putting PTEN in the Vault

The tumor suppressor protein PTEN dephosphorylates both proteins and phosphoinositide lipids and regulates many cellular processes including growth, motility, and apoptosis. Although a few PTEN-interacting proteins have been identified, its many putative regulatory domains suggest additional interactions that may affect PTEN function. Yu et al. have determined that PTEN interacts the vault complex, the largest known ribonucleoprotein particle described to date. Specifically, the C2 domain of PTEN interacts with two EF hands of the major vault protein (MVP), one of the three constituent proteins of the vault complex. Endogenous PTEN colocalized with vault complex particles when cell lysates were fractionated and both proteins immunoprecipitated when overexpressed in cultured cells. PTEN also associated with MVP in a calcium-dependent manner in vitro. The structure of the vault complex shows a hollow interior that is thought to facilitate transport and sequestration, or both, of proteins. The authors speculate that PTEN could get into the nucleus through its association with the vault complex. Z. Yu, N. Fotouhi-Ardakani, L. Wu, M. Maoui, S. Wang, D. Banville, S.-H. Shen, PTEN associates with the vault particles in HeLa cells. J. Biol. Chem. 277 , 40247-40252 (2002). [Abstract] [Full Text]

Putting PTEN in the Vault

The tumor suppressor protein PTEN dephosphorylates both proteins and phosphoinositide lipids and regulates many cellular processes including growth, motility, and apoptosis. Although a few PTEN-interacting proteins have been identified, its many putative regulatory domains suggest additional interactions that may affect PTEN function. Yu et al. have determined that PTEN interacts the vault complex, the largest known ribonucleoprotein particle described to date. Specifically, the C2 domain of PTEN interacts with two EF hands of the major vault protein (MVP), one of the three constituent proteins of the vault complex. Endogenous PTEN colocalized with vault complex particles when cell lysates were fractionated and both proteins immunoprecipitated when overexpressed in cultured cells. PTEN also associated with MVP in a calcium-dependent manner in vitro. The structure of the vault complex shows a hollow interior that is thought to facilitate transport and sequestration, or both, of proteins. The authors speculate that PTEN could get into the nucleus through its association with the vault complex.Z. Yu, N. Fotouhi-Ardakani, L. Wu, M. Maoui, S. Wang, D. Banville, S.-H. Shen, PTEN associates with the vault particles in HeLa cells. J. Biol. Chem. 277, 40247-40252 (2002). [Abstract] [Full Text]

Regulation of TRAIL Expression by the Phosphatidylinositol 3-Kinase/Akt/GSK-3 Pathway in Human Colon Cancer Cells

The intestinal mucosa is a rapidly-renewing tissue characterized by cell proliferation, differentiation, and eventual apoptosis with progression up the vertical gut axis. The inhibition of phosphatidylinositol (PI) 3-kinase by specific chemical inhibitors or overexpression of the lipid phosphatase PTEN enhances enterocyte-like differentiation in human colon cancer cell models of intestinal differentiation. In this report, we examined the role of PI 3-kinase inhibition in the regulation of apoptotic gene expression in human colon cancer cell lines HT29, HCT-116, and Caco-2. Inhibition of PI 3-kinase with the chemical inhibitor wortmannin increased TNF-related apoptosis-inducing ligand (TRAIL; Apo2) mRNA and protein expression. Similarly, overexpression of the tumor suppressor protein PTEN, an antagonist of PI 3-kinase signaling, resulted in the increased expression of TRAIL. Activation of PI 3-kinase by pretreatment with IGF-1, a gut trophic factor, markedly attenuated the induction of TRAIL by wortmannin. Moreover, overexpression of active Akt, a downstream target of PI 3-kinase, or inhibition of GSK-3, a downstream target of active Akt, completely blocked the induction of TRAIL by wortmannin. Consistent with findings that TRAIL is induced by agents that enhance intestinal cell differentiation, TRAIL expression was specifically localized to the differentiated cells of the colon and small bowel. Adenovirus-mediated overexpression of TRAIL increased DNA fragmentation of HCT-116 cells, demonstrating the functional activity of TRAIL induction. Taken together, our findings demonstrate induction of the TRAIL by inhibition of PI 3-kinase in colon cancer cell lines. These results identify TRAIL, a novel TNF family member, as a downstream target of the PI 3-kinase/Akt/GSK-3 pathway and may have important implications for better understanding the role of the PI 3-kinase pathway in intestinal cell homeostasis.

The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network.

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.

Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms.

Genetic alteration and loss of expression of tumor suppressor gene PTEN has been found in carcinomas of the breast, prostate, and endometrium, as well as in gliomas. PTEN expression in neural crest/neuroendocrine (NC/NE) tissues and in neoplasms has not been reported. This study examines PTEN expression in embryonal, fetal, and adult tissues by immunohistochemistry. The authors found high PTEN expression in embryonal, fetal, and adult NC/NE tissues. The authors also study the PTEN expression in NC/NE neoplasms (N = 37), including 5 melanocytic nevi, 2 melanomas, 9 carcinoids, 2 moderately differentiated neuroendocrine carcinomas, 13 poorly differentiated neuroendocrine carcinomas, 2 paragangliomas, 2 pheochromocytomas, 2 medullary thyroid carcinomas, and 1 neuroblastoma. All carcinoid tumors and melanocytic nevi showed moderate or strong immunostaining for PTEN. In contrast, the majority of poorly differentiated neuroendocrine carcinomas (7 of 13) were negative for PTEN (54%); the remainder showed diminished reactivity. The two melanomas studied were also negative for PTEN immunostaining. The paragangliomas, pheochromocytomas, medullary thyroid carcinomas, and neuroblastoma all showed a strong PTEN stain. The authors postulate that PTEN is a differentiation marker for NC/NE tissue and tumors and that loss of PTEN expression may represent an important step in the progression of NE tumors.

Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN.

Phosphatidylinositol (PI) 3-kinase signaling regulates numerous cellular processes, including proliferation, migration, and survival, which are required for neointimal hyperplasia and restenosis. The effectors of PI 3-kinase are activated by the phospholipid products of PI 3-kinase. In this report, we investigated the hypothesis that overexpression of the tumor suppressor protein PTEN, an inositol phosphatase specific for the products of PI 3-kinase, would inhibit the vascular smooth muscle cell (VSMC) responses necessary for neointimal hyperplasia and restenosis. Effects of PTEN were assessed in primary rabbit VSMCs after overexpression with a recombinant adenovirus and compared with uninfected or control virus-infected cells. PTEN was expressed endogenously in VSMCs, and PTEN overexpression inhibited PDGF-induced phosphorylation of p70(s6k), Akt, and glycogen synthase kinase-3-alpha and -beta but not ERK1 or -2. Overexpression of PTEN significantly inhibited both basal and PDGF-mediated VSMC proliferation and migration, the latter possibly due in part to downregulation of focal adhesion kinase. Moreover, PTEN overexpression induced cleavage of caspase-3 and significantly increased apoptosis compared with control cells. Taken together, these results demonstrate that PTEN overexpression potently inhibits the VSMC responses required for neointimal hyperplasia and restenosis. Adenovirus-expressed PTEN may therefore provide a useful tool for the local treatment of these and other vascular proliferative disorders.

Akt-ing Against a Loss

Mutations in the tumor suppressor protein PTEN occur in a variety of cancers. Its major enzymatic activity is to dephosphorylate phosphoinositides, including phosphoinositide-3,4,5-trisphosphate (PIP3). In the absence of PTEN, cellular levels of PIP3 increase, which result in overgrowth phenotypes and lethality in Drosophila larvae. However, PIP3 binds to numerous signaling molecules, and so it is not clear if there is a specific interaction that loss of PTEN function primarily affects. Stocker et al. show that flies can live in the absence of PTEN if the interaction of PIP3 with the serine-threonine kinase Akt is decreased through a mutation in its PH domain. At least in the fly, Akt appears to be the principal target of PIP3. H. Stocker, M. Andjelkovic, S. Oldham, M. Laffargue, M. P. Wymann, B. A. Hemmings, E. Hafen, Living with lethal PIP3 levels: Viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science 295 , 2088-2091 (2002). [Abstract] [Full Text]

PTEN Blocks Tumor Necrosis Factor-induced NF-κB-dependent Transcription by Inhibiting the Transactivation Potential of the p65 Subunit

PTEN is a lipid phosphatase responsible for down-regulating the phosphoinositide 3-kinase product phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate is involved in the activation of the anti-apoptotic effector target, Akt. Although the Akt pathway has been implicated in regulating NF-kappaB activity, it is controversial as to whether Akt activates NF-kappaB predominantly through mechanisms that regulate nuclear translocation or transactivation potential. In this report, we utilized PTEN as a natural biological inhibitor of Akt activity to study the effects on tumor necrosis factor (TNF)-induced activation of NF-kappaB. We found that the reintroduction of PTEN into prostate cells inhibited TNF-stimulated NF-kappaB transcriptional activity. PTEN failed to block TNF-induced IKK activation, IkappaBalpha degradation, p105 processing, p65 (RelA) nuclear translocation, and DNA binding of NF-kappaB. However, PTEN inhibited NF-kappaB-dependent transcription by blocking the ability of TNF to stimulate the transactivation domain of the p65 subunit. PTEN also inhibited the transactivation potential of the cyclic AMP-response element-binding protein, but this was not observed for c-Jun. The transactivation potential of p65 following TNF stimulation could be rescued from PTEN-dependent repression by re-introducing expression constructs encoding activated forms of phosphoinositide 3-kinase, Akt, or Akt and IKK. The ability of PTEN to inhibit the TNF-induced transactivation function of p65 is important, because expression of PTEN blocked TNF-stimulated NF-kappaB-dependent gene expression, thus sensitizing cells to TNF-induced apoptosis. Maintenance of the PTEN tumor suppressor protein is therefore required to modulate Akt activity and to concomitantly control the transcriptional activity of the anti-apoptotic transcription factor NF-kappaB.

PTEN Protects p53 from Mdm2 and Sensitizes Cancer Cells to Chemotherapy

The PTEN tumor suppressor protein inhibits phosphatidylinositol 3-kinase (PI3K)/Akt signaling that promotes translocation of Mdm2 into the nucleus. When restricted to the cytoplasm, Mdm2 is degraded. The ability of PTEN to inhibit the nuclear entry of Mdm2 increases the cellular content and transactivation of the p53 tumor suppressor protein. Retroviral transduction of PTEN into U87MG (PTEN null) glioblastoma cells increases p53 activity and expression of p53 target genes and induces cell cycle arrest. U87MG/PTEN glioblastoma cells are more sensitive than U87MG/PTEN null cells to death induced by etoposide, a chemotherapeutic agent that induces DNA damage. Previously, tumor suppressor proteins have been supposed to act individually to suppress cancers. Our results establish a direct connection between the activities of two major tumor suppressors and show that they act together to respond to stresses and malignancies. PTEN protects p53 from survival signals, permitting p53 to function as a guardian of the genome. By virtue of its capacity to protect p53, PTEN can sensitize tumor cells to chemotherapy that relies on p53 activity. p53 induces PTEN gene expression, and here it is shown that PTEN protects p53, indicating that a positive feedback loop may amplify the cellular response to stress, damage, and cancer.

Stem cells. PTEN--coupling tumor suppression to stem cells?

Mutations in the tumor suppressor protein PTEN are found in many different tumors. As Penninger and Woodgett discuss in their Perspective, new findings implicate PTEN in the control of neuronal cell size and in the proliferation and self-renewal of neuronal stem cells ( Groszer et al .). This surprising finding may yield both research and therapeutic benefits.