Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance 1 . The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-Kit mid CD3 + Lin − compartment, where unphosphorylated β-catenin is significantly increased. Conditional ablation of one allele of the β-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the β-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-Kit mid CD3 + Lin − LSCs and CD3 + leukaemic blasts,
The tumor suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) is frequently mutated or deleted in various human cancers. PTEN localizes predominantly to the cytoplasm and functions as a lipid phosphatase, thereby negatively regulating the phosphatidylinositol 3-kinase-AKT signaling pathway. PTEN can also localize to the nucleus, where it binds and regulates p53 protein level and transcription activity. However, the precise function of nuclear PTEN and the factors that control PTEN nuclear localization are still largely unknown. In this study, we identified oxidative stress as one of the physiological stimuli that regulate the accumulation of nuclear PTEN. Specifically, oxidative stress inhibits PTEN nuclear export, a process depending on phosphorylation of its amino acid residue Ser-380. Nuclear PTEN, independent of its phosphatase activity, leads to p53-mediated G 1 growth arrest, cell death, and reduction of reactive oxygen species production. Using xenografts propagated from human prostate cancer cell lines, we reveal that nuclear PTEN is sufficient to reduce tumor progression in vivo in a p53-dependent manner. The data outlined in this study suggest a unique role of nuclear PTEN to arrest and protect cells upon oxidative damage and to regulate tumorigenesis. Since tumor cells are constantly exposed to oxidative stress, our study elucidates the cooperative roles of nuclear PTEN with p53 in tumor suppression.The PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumor suppressor gene is mutated at high frequency in many primary human cancers and several cancer predisposition disorders (2). PTEN encodes a dually specific phosphatase that recognizes both lipid and peptide substrates (23), including phosphatidylinositol (3,4,5)-trisphosphate (PIP3), a product of phosphatidylinositol 3-kinase (PI3K). PTEN protein contains an N-terminal catalytic phosphatase domain (18, 32), a calcium-independent C2 domain (16), two PEST motifs, and a C-terminal PDZ binding domain (1). Several critical phosphorylation sites have been found in the PTEN C2 domain, including Ser-380, Thr-382, Thr-383, and Ser-385. Importantly, phosphorylation of these residues has been implicated to increase PTEN stability but decrease PTEN catalytic activity (36, 37).Although PTEN is localized mainly to the cytoplasm, it preferentially resides in the nucleus of differentiated or resting cells (15) as exemplified in MCF-7 cells (14), in which nuclear PTEN peaks in the G 1 phase and reaches a nadir in the S phase. Interestingly, changes in nuclear PTEN expression have also been observed in the endometrium during hormonal cycles (27). These data suggest that nuclear localization of PTEN is a dynamic process, associated with cell cycle, cell differentiation, and cellular functions. Decreased nuclear PTEN has been correlated with progressing thyroid carcinoma and melanoma (40), suggesting a functional role of nuclear PTEN in regulating tumorigenesis.Several studies have shown that PTEN nuclear localization depend...
The ability to traverse an intact nuclear envelope and productively infect nondividing cells is a salient feature of human immunodeficiency virus type 1 (HIV-1) and other lentiviruses, but the viral factors and mechanism of nuclear entry have not been defined. Partitioning of the eukaryotic genome into a separate cellular compartment is important for the regulation of cellular events, ranging from gene expression to cell cycle progression and cell activation. Controlling access to the genome may also serve to provide genetic stability and function as a potential deterrent to invading pathogens. Indeed, for many viruses that replicate in the nucleus, the nuclear envelope represents a significant barrier to establishing a productive infection. Circumvention and appropriation of nuclear import factors and pathways are strategies that viruses use to gain access to the nucleus (44).For retroviruses, nuclear import of the viral genome for the purpose of integration is a critical step in the viral life cycle (15). After cell entry and uncoating, the newly reverse transcribed viral genome exists with viral and host cell proteins in a large nucleoprotein complex termed the preintegration complex (PIC), which represents the subviral particle imported to the nucleus (reviewed in references 54 and 83). For most retroviral PICs, access to the nucleus takes place during cell division and the concomitant breakdown of the nuclear envelope. In contrast, the members of the lentivirus and alpharetrovirus subfamilies are able to productively infect nondividing cells, or cells arrested in the G 1 phase of the cell cycle, indicating that lentiviral and alpharetroviral PICs are able to traverse an intact nuclear envelope (37,48,80).The pathway and mechanism by which the lentiviral PIC crosses the nuclear envelope of an interphase cell are not clearly defined. Some components of the PIC have been hypothesized to confer a karyophilic property to the complex by bridging an interaction between the complex and cellular nuclear import factors (reviewed in reference 83). The identity or nature of such a factor is unknown, but viral integrase (IN) is a likely candidate due to its own karyophilic property and close association with the PIC (17, 47). In addition to IN, viral proteins matrix (MA) and Vpr, as well as the reverse transcription intermediate cDNA flap, are viral factors that have been studied for their role in PIC nuclear import. However, viruses mutated for both MA and Vpr are still capable of infecting nondividing cells (41, 51), and a definitive role for the cDNA flap in the nuclear import of the complex remains to be demonstrated (31, 56). More recently, the viral capsid protein (CA) has been reported to be the primary determinant for the nuclear import of human immunodeficiency virus type 1 (HIV-1) (30,100,102,103). However, a role for CA in nuclear import may reflect the importance of the proper uncoating of the core particle prior to nuclear translocation (101) as opposed to that of a mechanism for movement of the complex acr...
Multiple genetic or molecular alterations are known to be associated with cancer stem cell formation and cancer development. Targeting such alterations, therefore, may lead to cancer prevention. By crossing our previously established phosphatase and tensin homolog (Pten)-null acute T-lymphoblastic leukemia (T-ALL) model onto the recombination-activating gene 1 −/− background, we show that the lack of variable, diversity and joining [V(D)J] recombination completely abolishes the Tcrα/δ-c-myc translocation and T-ALL development, regardless of β-catenin activation. We identify mammalian target of rapamycin (mTOR) as a regulator of β-selection. Rapamycin, an mTOR-specific inhibitor, alters nutrient sensing and blocks T-cell differentiation from CD4 − CD8 − to CD4 + CD8 + , the stage where the Tcrα/δ-c-myc translocation occurs. Long-term rapamycin treatment of preleukemic Pten-null mice prevents Tcrα/δ-c-myc translocation and leukemia stem cell (LSC) formation, and it halts T-ALL development. However, rapamycin alone fails to inhibit mTOR signaling in the c-Kit mid CD3 + Lin − population enriched for LSCs and eliminate these cells. Our results support the idea that preventing LSC formation and selectively targeting LSCs are promising approaches for antileukemia therapies. T -lymphoblastic leukemia (T-ALL) is a common hematological malignancy that is associated with poor prognosis compared with other ALLs and is often fatal without effective treatment (1). Activating mutations in Notch gene homolog 1 (NOTCH1) are reported in 34-71% of human T-ALL patients (2, 3), whereas deletion or mutations of the phosphatase and tensin homolog (PTEN). tumor suppressor gene have recently been detected in 8-63% of pediatric T-ALL patients (3-6). The mutation status of NOTCH1 and PTEN can divide pediatric T-ALL patients into three groups: (i) those with both NOTCH1 and PTEN mutations, (ii) those with NOTCH1/F-box and WD repeat domain containing 7 (FBXW7) mutations, and (iii) those with only PTEN mutations (3). Interestingly, constitutive activation of the NOTCH signaling pathway is known to down-regulate PTEN expression (5, 7), suggesting that PTEN and its controlled PI3K/v-akt murine thymoma viral oncogene homolog (AKT)/mTOR pathway are critical for the etiology of human T-ALL. Furthermore, PTEN deletion seems to be correlated with poor response to chemotherapy (6) and resistance to pharmacological inhibition of NOTCH1 (5). Therefore, understanding the molecular mechanisms of PTEN-mediated T-ALL pathogenesis and drug resistance is a critical step to improving T-ALL therapeutics.To investigate the molecular and cellular mechanisms associated with PTEN-controlled T-ALL pathogenesis and therapeutic resistance, we have recently developed a Pten loxP/loxP ;VE-CadherinCre + ;Rosa26 loxP-stop-loxP -LacZ + (Pten null) T-ALL mouse model by conditional deletion of Pten in a subset of fetal liver hematopoietic stem cells (8). The resulting animals develop a transient myeloproliferative disorder followed by T-ALL with 100% penetrance. Besides Pt...
Cilia are hair-like cellular protrusions important in many aspects of eukaryotic biology. For instance, motile cilia enable fluid movement over epithelial surfaces, while primary (sensory) cilia play roles in cellular signalling. The molecular events underlying cilia dynamics, and particularly their disassembly, are not well understood. Phosphatase and tensin homologue (PTEN) is an extensively studied tumour suppressor, thought to primarily act by antagonizing PI3-kinase signalling. Here we demonstrate that PTEN plays an important role in multicilia formation and cilia disassembly by controlling the phosphorylation of Dishevelled (DVL), another ciliogenesis regulator. DVL is a central component of WNT signalling that plays a role during convergent extension movements, which we show here are also regulated by PTEN. Our studies identify a novel protein substrate for PTEN that couples PTEN to regulation of cilia dynamics and WNT signalling, thus advancing our understanding of potential underlying molecular etiologies of PTEN-related pathologies.
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