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Molecular Biology, Pathobiology and Genetics |
1 The Wistar Institute, Philadelphia, Pennsylvania and 2 Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, Stanford, California
Requests for reprints: Anthony J. Capobianco, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: 215-495-6816; Fax: 215-495-6819; E-mail: acapobianco{at}wistar.upenn.edu.
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Abstract |
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Introduction |
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The tumor suppressor protein p53 plays a critical role in maintaining cellular homeostasis both in normal development and following various cellular stresses, including DNA damage and nutrient deprivation (13–15). Activation of p53 directs cells to undergo cell cycle arrest and/or apoptosis depending on the type and extent of the stimulus. Regulation of p53 turnover is largely mediated by the ubiquitin ligase mdm2, which is the primary negative regulator of p53 (16–18). Furthermore, expression of ARF, which binds to and inhibits the activity of mdm2, leads to activation of p53 (19, 20). It is thought that the ARF-mdm2-p53 pathway acts as a tumor surveillance mechanism that is activated in response to inappropriately sustained proliferative signals (21, 22). Therefore, many oncogenes cause an inherent apoptotic response that places a selective pressure on mutating this surveillance mechanism. This is apparent from the observation that all three genes in the pathway are commonly mutated in cancers, which ultimately leads to inactivation of p53 function (23–26).
Herein, we report the finding that Notch signaling suppresses p53 activity during leukemogenesis. Following inactivation of Notch signaling, p53 protein levels accumulate and cells rapidly initiate an apoptotic program. Inhibition of the mdm2-p53 interaction by ionizing radiation or Nutlin is sufficient to activate p53 in Nic lymphoma. This indicates that p53 protein levels are suppressed by a mechanism involving mdm2-dependent degradation of p53. In support of this model, we show that Notch-induced lymphomas do not express ARF. Furthermore, we show that efficient regression of Nic-induced lymphoma requires p53 activity. Although inactivation of the Nic transgene leads to tumor regression, 100% of mice relapse within 6 weeks. Interestingly, in a majority of the relapsed tumors the Notch transgene is reactivated, indicating that there is a strong selective pressure to reacquire Notch activity. Therefore, suppression of p53 by Notch is an important event in the development of lymphoma and the activation of p53 mediates regression of disease.
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Materials and Methods |
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Tumorigenesis assays. Mice that were either compound hemizygous for tTA-Nic or hemizygous Top-Notchic mice were monitored for up to 1 year for signs of hematopoietic disease. Mice that were given doxycycline were maintained on 100 µg/mL in the drinking water. Single-cell suspensions of leukemia cells were prepared by standard procedures. RBC were lysed in RBC lysis buffer (150 mmol/L NH4Cl, 10 mmol/L KHCO3, and 10 µmol/L EDTA) for 10 minutes on ice.
Flow cytometry. Single-cell suspensions were used for all fluorescence-activated cell sorting (FACS) analysis. Antibodies for flow cytometry were obtained from PharMingen (San Jose, CA) and used as indicated by supplier. Cells were analyzed in the FACSCalibur (Becton Dickinson, Franklin Lakes, NJ) using Cellquest software. Data shown is representative of multiple mice.
Protein analysis. Tissues from indicated mice were pulverized in liquid nitrogen using mortar and pestle. Protein extracts were prepared by lysis of cells in standard lysis buffer and proteins were detected using standard techniques as previously described (28). Size exclusion chromatography was done as described using an AKTA fast protein liquid chromatography system, as previously described (10).
Southern blot analysis. Southern blot analysis was done using standard techniques.
Reverse transcription-PCR analysis. RNA was extracted from tumor samples using Trizol (Invitrogen, Carlsbad, CA) following the manufacturer's protocol. Total RNA (2 µg) was used to produce cDNA in a 20 µL reaction using MLV reverse transcriptase (Promega, Madison, WI) according to manufacturer's specifications.
Cell culture and in vitro studies. Molt-3, SUP-T1, and Jurkat were obtained from American Type Culture Collection (Manassas, VA). NA1 were provided by K. Georgopoulos (Massachusetts General Hospital, Charlestown, MA). Cell lines were maintained in RPMI supplemented with 10% fetal bovine serum, 100 units/mL penicillin, 100 µg/mL streptomycin, and 2 mmol/L glutamine. Cells were treated with 5 µmol/L Nutlin (Cayman Chemical, Ann Arbor, MI), 200 nmol/L wortmanin (Sigma, St. Louis, MO), 10 µmol/L UO126 (EMD Biosciences, San Diego, CA), or 25 µmol/L MG132 (EMD Biosciences) all prepared in DMSO for the indicated times.
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Results |
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promoter (EµSR-tTA). The EµSR-tTA has been previously described and expresses the tTA in T cells, leading to tissue type–specific activation of genes placed under the control of the tetracycline operator sequences (27). Resulting offspring included hemizygous Top-Notchic and compound hemizygous Top-Notchic/EµSR-tTA (tTA-Nic) mice on an inbred FVB/n background. Offspring were monitored for up to 1 year for signs of hematopoietic disease. A cohort of compound hemizygous mice was given doxycycline in their drinking water to suppress expression of the Top-Notchic transgene. tTA-Nic mice not treated with doxycycline developed aggressive leukemia/lymphoma with a median onset of disease of 
30 weeks with the earliest onset of 7 weeks after birth (Fig. 1A). By 1 year of age, 60% of tTA-Nic mice succumb to disease in the absence of doxycycline. Visual autopsy of leukemic tTA-Nic mice revealed gross splenomeglia, enlarged lymph nodes, and thymic involvement compared with disease-free Top-Notchic mice (Fig. 1B). Western blot analysis of thymocytes (t) and splenocytes (s) from leukemic tTA-Nic mice using an affinity purified Notchic antibody showed high levels of Nic expression (Fig. 1C). FACS analysis of splenocytes from Top-Notchic mice revealed normal ratios of mature CD4+ and CD8+ single-positive T cells in the periphery (Fig. 1C). In contrast, nearly all splenic-derived lymphocytes in the tTA-Nic mice were immature CD4+/CD8+ double-positive T cells, which is a diagnostic characteristic of leukemia (Fig. 1C). Histologic analysis of tissues obtained from tTA-Nic leukemic mice showed effacement of the spleen, bone marrow, and thymus with leukemic T cells. The liver also contained numerous focal sites of lymphoma (see Supplementary Fig. S1A).
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tTA-Nic leukemia cells require sustained Notch expression. To address if leukemic cells derived from tTA-Nic mice are dependent on the continuous expression of the Top-Notchic transgene, we did leukemia transplant experiments. tTA-Nic mice that were moribund due to lymphoma were euthanized and single-cell suspensions were prepared from lymphoid organs. For these experiments, 5 x 105 cells were transplanted i.v. into the tail vein of multiple nontransgenic FVB/n mice. Cohorts of recipient mice were either treated with doxycycline or received no treatment. Recipient mice that were not treated with doxycycline developed T-cell leukemia by 12 weeks of age, whereas mice maintained on doxycycline in the drinking water remained disease free. Moreover, a single dose of doxycycline (250 µg) injected i.p. on the day following transplant, was sufficient to inhibit tumor formation in all experiments (n = 4, data not shown). Gross autopsy of mice that succumb to disease in the absence of doxycycline displayed a similar phenotype compared with the primary leukemic mice (Fig. 2A). This result also shows that the disease is an authentic lymphoma and not simply a lymphoproliferative disease. Western blot analysis showed the absence of Nic expression from the transgene in the doxycycline-treated mice, whereas nontreated mice expressed the transgene (Fig. 2B). As before, examination of CD4 and CD8 T-cell surface markers on splenocytes displayed an accumulation of immature CD4+/CD8+ double-positive T cells (Fig. 2C). Leukemic cells acquired from this analysis were then transplanted into 3- to 6-week-old nontransgenic recipients in the presence or absence of doxycycline for up to five serial passages. For each passage, leukemogenesis in the transplanted animals maintained the requirement for Nic expression (data not shown). This finding is consistent with our previous observation, in vitro, that tamoxifen-regulated ER-Nic-transformed RKE cells maintain the requirement for activated Notch (29).
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Rapid regression is accompanied by apoptosis. To address the mechanism of regression, multiple mice were injected i.v. with 1 x 106 cells from the same primary lymphoma and allowed to develop signs of advanced disease. Mice were then given doxycycline and regression of disease was analyzed over a time course beginning at 6 hours after administration of doxycycline. The most striking sign of disease regression is the marked decrease in the overall size of the spleen within 4 days following doxycycline treatment, as shown by gross autopsy at each time point (Fig. 3A). Nic expression is extinguished within 6 hours of administration of doxycycline, as determined by the analysis of both protein and mRNA levels (Fig. 3B). Furthermore, regression was analyzed at a cellular level using flow cytometry to follow both apoptosis and T-cell differentiation over a time course following administration of doxycycline (Fig. 3B). We observed a wave of apoptotic cells as measured by an increase in Annexin V–positive staining cells that peaked at 36 hours after initiation of continuous doxycycline treatment. The increase in the percentage of cells undergoing apoptosis was observed in all hematopoietic organs including thymus, spleen, lymph nodes, and bone marrow (Fig. 3B; data not shown). Notch-induced leukemias have a characteristic CD4+/CD8+ dual-positive immature T-cell phenotype; therefore, we examined the CD4 and CD8 status of T cells in the periphery following doxycycline administration to determine if mature single-positive T cells were able to develop. We observed a gradual increase in normally differentiated TCR-positive cells in the periphery throughout the time course, beginning as early as 24 hours (Fig. 3B; data not shown). The brisk appearance of normal CD4+ and CD8+ single-positive T cells in the periphery might indicate that following inactivation of Notch there is a dual wave of apoptosis and differentiation that occurs following inactivation of Nic expression.
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Notch suppresses p53. To identify the molecular mechanism of apoptotic death that occurs following inactivation of the Notch transgene, we examined the status of the tumor suppressor protein p53. To address the role of p53 in regression of Nic-induced lymphoma, multiple mice were transplanted with a single primary leukemia and were allowed to develop advanced disease. Doxycycline was then given and two mice were euthanized at each time point following the initiation of doxycycline treatment. At the time of treatment (T = 0), the tumors displayed high levels of Nic expression and nearly undetectable levels of p53. Over the course of the experiment, there was a dramatic increase in p53 protein level that began to emerge at 24 hours and peaked at 36 hours after initiation of doxycycline treatment (Fig. 4A). The increase in p53 protein levels is concomitant with the increase in the percentage of apoptotic cells, suggesting that p53 may be instructing the apoptotic program following inhibition of Notch signaling (Fig. 3B). To further characterize the relationship between Notch signaling and p53, we did Western blot analysis on a panel of primary tTA-Nic tumors (Fig. 4B). Nearly all tumors displayed high levels of Nic protein and low or undetectable levels of p53 protein. This indicates that Notch activity has a role in regulating p53 protein stability. To genetically examine the relationship between Nic and p53, mice that were compound double hemizygous for both the Top-Notchic and tTA transgenes were mated with mice heterozygous for p53 (30). The resulting offspring included mice that were compound hemizygous for Top-Notchic and tTA (tTA-Nic) or mice compound hemizygous for Top-Notchic and tTA and heterozygous for p53 (tTA-Nic/p53+/–) in an F1 hybrid FVB/129 background. Kaplan-Meier analysis of the offspring from these matings showed that onset of disease was unaffected by p53 status (Fig. 4C). Analysis of the expression levels of Nic and p53 revealed that tumors expressed Nic but did not express p53. Loss of heterozygosity (LOH) at the wild-type allele of p53 is typically associated with progression of tumorigenesis in many model systems. Although all the tTA-Nic and tTA-Nic/p53+/– mice displayed expression of p53 mRNA, we analyzed the p53 genomic locus for LOH by Southern blot analysis. We examined a tTA-Nic and a tTA-Nic/p53+/– mouse that succumbed to disease with the quickest onset and observed no LOH, indicating that there is no selective pressure to lose the p53 locus during Nic-induced tumorigenesis (Fig. 4D). These data further supports the hypothesis that Notch signaling suppresses p53 function during the progression of disease.
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Discussion |
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Oncogene addiction. In the Top-Notchic model, 100% of mice relapse with neoplastic disease following inactivation of Notch, the initiating oncogene. Interestingly, in a majority of the relapsed tumors Notch expression was reactivated, indicating a strong selective pressure for Notch activity (Fig. 3). In contrast, other tumor models have dramatically different relapse kinetics and characteristics. For example, the Felsher group reported that expression of c-myc under control of the EµSR-tTA leads to T-cell lymphoma (27). The EµSR-tTA mouse strain used in that study is the same as the one we used in our experiments. They reported in their study that inactivation of c-myc expression in tumors results in regression and that only 20% of mice relapse with disease after a protracted latency (32). Furthermore, none of the relapsed tumors expressed the human c-myc transgene, indicating that relapse is due to newly acquired mutations and not reactivation of the myc transgene. The contrast in the kinetics and characteristics of lymphoma relapse in the myc and Notch models raises two important points. First, c-myc-induced lymphoma have a low potential to relapse, in terms of both latency and incidence (20%), indicating the mice enter a state of disease "remission." However, Notch-induced lymphoma invariably relapse with rapid kinetics following inhibition of the transgene, indicating that these tumors do not enter a state of prolonged disease remission. Second, whereas Notch-induced tumors display a strict requirement for Notch activity, Myc-induced tumors do not seem to reactivate Myc expression in relapsed tumors. Therefore, this leads one to conclude that addiction to the initiating oncogene greatly depends on the particular oncogene. However, does the tissue type of the tumor influence the dependence on the initiating oncogene? The Chodosh group has reported that c-myc-induced mammary adenocarcinomas also regress following inactivation of the myc transgene, but the kinetics and dependence on myc expression is not the same as that reported for T-cell lymphoma (33). Many of these tumors incompletely regress and harbor a mutation in the Kras2 gene that is thought to exist in the tumor before attenuation of transgene expression. These tumors never reactivate the transgene and display a resurgence in tumor growth within 40 days of myc inactivation. Tumors from this study that do completely regress also eventually relapse; however, with a protracted latency and incomplete penetrance, such that of mice that are monitored for >1 year on doxycycline 50% relapse with disease. Again, in contrast to the Notch model, only 20% of these relapsed tumors express the c-myc transgene.
What is the driving force for the relapse of neoplastic disease in these mouse models? Several issues come to mind when considering this question; the issues of genomic instability, tumor burden, and cancer stem cells, among others. Using a serial transplantation assay, we clearly showed that tumor burden is linked to relapse of disease in the Top-Notchic model. For example, if a single-cell suspension (1 x 106 cells), prepared from a Nic lymphoma, is transplanted into a naive recipient mouse, the cells are not capable of tumor formation if Notch signaling is attenuated the day following transplantation (Fig. 2). In contrast, treatment of a mouse with late stage disease results in relapse with a frequency of 100%. Furthermore, after multiple (5) serial transplants of a single tTA-Nic lymphoma, cells never lost sensitivity to doxycycline, indicating that even after multiple cycles of tumor formation cells never emerged that were insensitive to doxycycline, providing evidence that mutation drives relapse and not cancer stem cells in the Top-Notchic model. Therefore, we propose that in the case of Notch, the driving force in relapse is the generation of an environment that is conducive to mutations by massive cell death and large tumor burden. Moreover, Notch does not inherently induce genomic instability but that genomic instability is a consequence of the environment. In contrast, Myc drives genomic instability, which results in the accumulation of mutations throughout the initiation of neoplastic disease; this hypothesis is supported by the report from the Felsher and Chodosh groups (33).
Regulation of p53 activation by Notch. In this report, we show that Notch suppresses p53 in lymphomagenesis. We derive this conclusion from several lines of evidence. Western blot analysis of a panel of primary Nic-induced lymphoma showed that nearly all Nic-induced tumors have undetectable levels of p53 protein (Fig. 6A). Furthermore, p53 is not mutated in these tumors as shown by the fact that p53 is activated following treatment with 
-irradiation, Nutlin, or immediately following inactivation of the Notch transgene (Figs. 6 and 4). These results strongly indicate that Notch plays a direct role in regulating p53 stability.
To secure a genetic proof to the hypothesis that Notch is suppressing p53 in lymphomagenesis, we examined the effect of mutant p53 on the latency and penetrance of Notch-induced tumor formation. To do this we created a mouse line that harbors the Top-Notchic transgene on a p53+/– background. For most oncogenes, such as Myc and Wnt-1, a p53+/– background dramatically accelerates tumor formation concomitant with LOH at the p53 locus (34–36). In contrast, p53 status had no observable effect on tumor initiation or progression by Notch. Furthermore, there was no LOH at the p53 locus in tumors from these mice (Fig. 4D). The clear lack of selective pressure to lose p53 in the Notch model strongly supports our hypothesis that Notch is actively suppressing p53 in lymphomagenesis.
How does Notch suppress p53 activity in lymphomagenesis? We propose that suppression of p53 by Nic is mediated through an mdm2-dependent mechanism. We draw this conclusion from several experiments. Because we did not observe any decrease in the mRNA levels of p53, we reasoned that p53 must be suppressed by a proteolytic mechanism. In support of this notion, treatment of lymphoma cells with the proteosome inhibitor MG-132 leads to a rapid accumulation of p53 (Fig. 6). Because mdm2 is the primary factor leading to destruction of p53, we sought to examine the status of the mdm2-p53 connection. Using cell lines derived from human and mouse T-cell lymphomas with activated Notch, as well as tTA-Nic lymphoma, we showed that the mdm2-p53 pathway is indeed intact. We showed this by inhibiting the interaction of mdm2 and p53 with two well-characterized stimuli, -irradiation and Nutlin. Treatment of cells with these agents dramatically induced p53 levels and apoptosis, indicating that p53 is being held in check by mdm2. These data strongly support the hypothesis that Notch is suppressing p53 via an mdm2 mechanism. Consistent with this hypothesis, we show that tTA-Nic tumors do not express ARF protein. A lack of ARF protein would lead to the constitutive degradation of p53 by mdm2. However, we cannot rule out the possibility that Notch affects p53 stability by an mdm2-independent mechanism. Because Notch suppresses p53, there is no selective pressure against components of the Arf-Mdm2-p53 pathway. Therefore, the possibility remains that Notch could inhibit p53 via a yet to be characterized pathway while leaving the Arf-mdm2-p53 pathway intact, therefore creating, in effect, two independent pools of p53. In such a scenario, we would expect to be able to activate p53 by inhibiting the mdm2-p53 interaction. Considering this possibility, we have examined the expression of Cop1 and Pirh2 and did not observed any changes in mRNA levels (data not shown). However, we also investigated effects on mdm2 and we did not observe and significant differences. Reports in the literature have suggested that Notch affects aspects of mdm2 function, but we failed to reproduce these in our studies (37). Therefore, the precise mechanism for the suppression of p53 by Notch remains elusive, but it seems that the likely mechanism is through disruption of the Arf-mdm2-p53 tumor surveillance pathway. Regardless of the mechanism, our study reveals that inhibition of the mdm2-p53 interaction is sufficient to cause accumulation of p53 and induce apoptosis and thereby provides a rational basis for treatment of Notch-positive tumors.
Clinical implications. How does the ability of Notch to suppress p53 in lymphomagenesis pertain to human T-ALL? In a survey of pediatric T-ALL, the Hayashi group found that only 5% (3 of 57) patients harbored mutations in the p53 gene, indicating that suppression of p53, rather than mutation of the p53 gene might be a more common event in human T-ALL (38). However, in this same study they reported that 67% (12 of 18) of established T-ALL cell lines had mutations in p53, representing a fundamental difference between primary samples and cell lines. Consistent with this study only one (6%, 1 of 15) of primary tTA-Nic lymphomas expressed a potential mutated p53 (Fig. 4B). We propose that the high incidence of Notch mutations in patients contributes to the low incidence of p53 mutations in T-ALL patients. Accordingly, we show that p53 is capable of being activated and cause apoptosis of Notch expressing lymphoma cells. We propose that therapeutics designed to activate p53 by specifically inhibiting its proteolytic degradation will be an effective class of treatments for patients with mutated Notch. To this end, we show that treatment of Notch expressing cell lines or Notch-expressing lymphoma with the small molecule Nutlin or ionizing radiation leads to cell death through a p53-dependent apoptotic program (Fig. 6). This line of experiments provides a proof-of-principle for this class of therapeutics and shows that if suppression of p53 is overcome, Notch expressing tumor cells can be eradicated.
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank the members of the Capobianco Laboratory for support and technical assistance during this work.
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Footnotes |
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L.J. Beverly is a graduate student in the Department of Molecular Genetics, Biochemistry, and Microbiology at the University of Cincinnati School of Medicine. This article is in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Received 5/16/05. Revised 6/ 1/05. Accepted 6/13/05.
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References |
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and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci U S A 2002;99:3788–93.This article has been cited by other articles:
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  E. J. Volanakis, R. T. Williams, and C. J. Sherr Stage-specific Arf tumor suppression in Notch1-induced T-cell acute lymphoblastic leukemia Blood, November 12, 2009; 114(20): 4451 - 4459. [Abstract] [Full Text] [PDF]
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 O. Meurette, S. Stylianou, R. Rock, G. M. Collu, A. P. Gilmore, and K. Brennan Notch Activation Induces Akt Signaling via an Autocrine Loop to Prevent Apoptosis in Breast Epithelial Cells Cancer Res., June 15, 2009; 69(12): 5015 - 5022. [Abstract] [Full Text] [PDF]
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 C. Wang, R. Qi, N. Li, Z. Wang, H. An, Q. Zhang, Y. Yu, and X. Cao Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression J. Biol. Chem., June 12, 2009; 284(24): 16183 - 16190. [Abstract] [Full Text] [PDF]
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I. Joshi, L. M. Minter, J. Telfer, R. M. Demarest, A. J. Capobianco, J. C. Aster, P. Sicinski, A. Fauq, T. E. Golde, and B. A. Osborne Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases Blood, February 19, 2009; 113(8): 1689 - 1698. [Abstract] [Full Text] [PDF]
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P. Rizzo, H. Miao, G. D'Souza, C. Osipo, J. Yun, H. Zhao, J. Mascarenhas, D. Wyatt, G. Antico, L. Hao, et al. Cross-talk between Notch and the Estrogen Receptor in Breast Cancer Suggests Novel Therapeutic Approaches Cancer Res., July 1, 2008; 68(13): 5226 - 5235. [Abstract] [Full Text] [PDF]
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C. W. Lee, C. M. Raskett, I. Prudovsky, and D. C. Altieri Molecular Dependence of Estrogen Receptor-Negative Breast Cancer on a Notch-Survivin Signaling Axis Cancer Res., July 1, 2008; 68(13): 5273 - 5281. [Abstract] [Full Text] [PDF]
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 B. W. Purow, T. K. Sundaresan, M. J. Burdick, B. A. Kefas, L. D. Comeau, M. P. Hawkinson, Q. Su, Y. Kotliarov, J. Lee, W. Zhang, et al. Notch-1 regulates transcription of the epidermal growth factor receptor through p53 Carcinogenesis, May 1, 2008; 29(5): 918 - 925. [Abstract] [Full Text] [PDF]
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 S. Matsuoka, Y. Oike, I. Onoyama, A. Iwama, F. Arai, K. Takubo, Y. Mashimo, H. Oguro, E. Nitta, K. Ito, et al. Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL Genes & Dev., April 15, 2008; 22(8): 986 - 991. [Abstract] [Full Text] [PDF]
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 K. Podsypanina, K. Politi, L. J. Beverly, and H. E. Varmus Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras PNAS, April 1, 2008; 105(13): 5242 - 5247. [Abstract] [Full Text] [PDF]
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C. Spaulding, E. J. Reschly, D. E. Zagort, Y. Yashiro-Ohtani, L. J. Beverly, A. Capobianco, W. S. Pear, and B. L. Kee Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas Blood, October 1, 2007; 110(7): 2650 - 2658. [Abstract] [Full Text] [PDF]
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K. Lefort, A. Mandinova, P. Ostano, V. Kolev, V. Calpini, I. Kolfschoten, V. Devgan, J. Lieb, W. Raffoul, D. Hohl, et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK{alpha} kinases Genes & Dev., March 1, 2007; 21(5): 562 - 577. [Abstract] [Full Text] [PDF]
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 V. M. Sharma, J. A. Calvo, K. M. Draheim, L. A. Cunningham, N. Hermance, L. Beverly, V. Krishnamoorthy, M. Bhasin, A. J. Capobianco, and M. A. Kelliher Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc Mol. Cell. Biol., November 1, 2006; 26(21): 8022 - 8031. [Abstract] [Full Text] [PDF]
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E. J. Reschly, C. Spaulding, T. Vilimas, W. V. Graham, R. L. Brumbaugh, I. Aifantis, W. S. Pear, and B. L. Kee Notch1 promotes survival of E2A-deficient T cell lymphomas through pre-T cell receptor-dependent and -independent mechanisms Blood, May 15, 2006; 107(10): 4115 - 4121. [Abstract] [Full Text] [PDF]
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K. G. Leong and A. Karsan Recent insights into the role of Notch signaling in tumorigenesis Blood, March 15, 2006; 107(6): 2223 - 2233. [Abstract] [Full Text] [PDF]
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