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Dive into the research topics where Maria S. Soengas is active.

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Featured researches published by Maria S. Soengas.


Nature | 2005

BRAFE600-associated senescence-like cell cycle arrest of human naevi

Chrysiis Michaloglou; Liesbeth C.W. Vredeveld; Maria S. Soengas; Christophe Denoyelle; Thomas Kuilman; Chantal M.A.M. van der Horst; Donné M. Majoor; Jerry W. Shay; Wolter J. Mooi; Daniel S. Peeper

Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16INK4a (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes; however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi (moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations (predominantly V600E, where valine is substituted for glutamic acid) in BRAF, a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma). This raises the question of whether naevi undergo BRAFV600E-induced senescence. Here we show that sustained BRAFV600E expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16INK4a and senescence-associated acidic β-galactosidase (SA-β-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-β-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16INK4a, suggesting that factors other than p16INK4a contribute to protection against BRAFV600E-driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAFV600E-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.


Cell | 1998

Differential requirement for caspase 9 in apoptotic pathways in vivo.

Razqallah Hakem; Anne Hakem; Gordon S. Duncan; Jeffrey T. Henderson; Minna Woo; Maria S. Soengas; Andrew Elia; José Luis de la Pompa; David Kagi; Wilson Khoo; Julia Potter; Ritsuko Yoshida; Stephen Kaufman; Scott W. Lowe; Josef M. Penninger; Tak W. Mak

Mutation of Caspase 9 (Casp9) results in embryonic lethality and defective brain development associated with decreased apoptosis. Casp9-/- embryonic stem cells and embryonic fibroblasts are resistant to several apoptotic stimuli, including UV and gamma irradiation. Casp9-/- thymocytes are also resistant to dexamethasone- and gamma irradiation-induced apoptosis, but are surprisingly sensitive to apoptosis induced by UV irradiation or anti-CD95. Resistance to apoptosis is accompanied by retention of the mitochondrial membrane potential in mutant cells. In addition, cytochrome c is translocated to the cytosol of Casp9-/- ES cells upon UV stimulation, suggesting that Casp9 acts downstream of cytochrome c. Caspase processing is inhibited in Casp9-/- ES cells but not in thymocytes or splenocytes. Comparison of the requirement for Casp9 and Casp3 in different apoptotic settings indicates the existence of at least four different apoptotic pathways in mammalian cells.


Nature | 2001

Inactivation of the apoptosis effector Apaf-1 in malignant melanoma

Maria S. Soengas; Paola Capodieci; David Polsky M.D.; Jaume Mora; Manel Esteller; Ximena Opitz-Araya; Richard McCombie; James G. Herman; William L. Gerald; Yuri Lazebnik; Carlos Cordon-Cardo; Scott W. Lowe

Metastatic melanoma is a deadly cancer that fails to respond to conventional chemotherapy and is poorly understood at the molecular level. p53 mutations often occur in aggressive and chemoresistant cancers but are rarely observed in melanoma. Here we show that metastatic melanomas often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. Loss of Apaf-1 expression is accompanied by allelic loss in metastatic melanomas, but can be recovered in melanoma cell lines by treatment with the methylation inhibitor 5-aza-2′-deoxycytidine (5aza2dC). Apaf-1-negative melanomas are invariably chemoresistant and are unable to execute a typical apoptotic programme in response to p53 activation. Restoring physiological levels of Apaf-1 through gene transfer or 5aza2dC treatment markedly enhances chemosensitivity and rescues the apoptotic defects associated with Apaf-1 loss. We conclude that Apaf-1 is inactivated in metastatic melanomas, which leads to defects in the execution of apoptotic cell death. Apaf-1 loss may contribute to the low frequency of p53 mutations observed in this highly chemoresistant tumour type.


Oncogene | 2003

Apoptosis and melanoma chemoresistance

Maria S. Soengas; Scott W. Lowe

Melanoma is the most aggressive form of skin cancer and is notoriously resistant to all current modalities of cancer therapy. A large set of genetic, functional and biochemical studies suggest that melanoma cells become ‘bullet proof’ against a variety of chemotherapeutic drugs by exploiting their intrinsic resistance to apoptosis and by reprogramming their proliferation and survival pathways during melanoma progression. In recent years, the identification of molecules involved in the regulation and execution of apoptosis, and their alteration in melanoma, have provided new insights into the molecular basis for melanoma chemoresistance. With this knowledge in hand, the challenge is now to devise strategies potent enough to compensate or bypass these cell death defects and improve the actual poor prognosis of patients at late stages of the disease.


Nature Cell Biology | 2006

Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway

Christophe Denoyelle; George Abou-Rjaily; Vladimir Bezrookove; Monique Verhaegen; Timothy M. Johnson; Douglas R. Fullen; Jenny N. Pointer; Stephen B. Gruber; Lyndon D. Su; Mikhail A. Nikiforov; Randal J. Kaufman; Boris C. Bastian; Maria S. Soengas

Dysfunction of the endoplasmic reticulum (ER) has been reported in a variety of human pathologies, including cancer. However, the contribution of the ER to the early stages of normal cell transformation is largely unknown. Using primary human melanocytes and biopsies of human naevi (moles), we show that the extent of ER stress induced by cellular oncogenes may define the mechanism of activation of premature senescence. Specifically, we found that oncogenic forms of HRAS (HRASG12V) but not its downstream target BRAF (BRAFV600E), engaged a rapid cell-cycle arrest that was associated with massive vacuolization and expansion of the ER. However, neither p53, p16INK4a nor classical senescence markers – such as foci of heterochromatin or DNA damage – were able to account for the specific response of melanocytes to HRASG12V. Instead, HRASG12V-driven senescence was mediated by the ER-associated unfolded protein response (UPR). The impact of HRAS on the UPR was selective, as it was poorly induced by activated NRAS (more frequently mutated in melanoma than HRAS). These results argue against premature senescence as a converging mechanism of response to activating oncogenes and support a direct role of the ER as a gatekeeper of tumour control.


Cancer Research | 2005

Differential regulation of Noxa in normal melanocytes and melanoma cells by proteasome inhibition: Therapeutic implications

Yolanda Fernández; Monique Verhaegen; Thomas P. Miller; Jenny Rush; Philipp Steiner; Anthony W. Opipari; Scott W. Lowe; Maria S. Soengas

Melanoma is the most aggressive form of skin cancer and advanced stages are invariably resistant to conventional therapeutic agents. Using bortezomib as a prototypic proteasome inhibitor, we have identified a novel and critical role of the proteasome in the maintenance of the malignant phenotype of melanoma cells that could have direct translational implications. Thus, melanoma cells from early, intermediate, and late stages of the disease could not sustain proteasome inhibition and underwent an effective activation of caspase-dependent and -independent death programs. This effect was tumor cell selective, because under similar conditions, normal melanocytes remained viable. Intriguingly, and despite of interfering with a cellular machinery in charge of controlling the half-life of the vast majority of cellular proteins, bortezomib did not promote a generalized disruption of melanoma-associated survival factors (including NF-kappaB, Bcl-2, Bcl-x(L), XIAP, TRAF-2, or FLIP). Instead, we identified a dramatic induction in vitro and in vivo of the BH3-only protein Noxa in melanoma cells (but not in normal melanocytes) in response to proteasome inhibition. RNA interference validated a critical role of Noxa for the cytotoxic effect of bortezomib. Notably, the proteasome-dependent regulation of Noxa was found to extend to other tumor types, and it could not be recapitulated by standard chemotherapeutic drugs. In summary, our results revealed Noxa as a new biomarker to gauge the efficacy of bortezomib specifically in tumor cells, and provide a new strategy to overcome tumor chemoresistance.


Cancer Research | 2007

An Organometallic Protein Kinase Inhibitor Pharmacologically Activates p53 and Induces Apoptosis in Human Melanoma Cells

Keiran S.M. Smalley; Rooha Contractor; Nikolas K. Haass; Angela N. Kulp; G. Ekin Atilla-Gokcumen; Douglas S. Williams; Howard Bregman; Keith T. Flaherty; Maria S. Soengas; Eric Meggers; Meenhard Herlyn

Unlike other tumors, melanomas harbor wild-type (WT) p53 but exhibit impaired p53-dependent apoptosis. The mechanisms for the impaired p53 activation are poorly understood but may be linked to the high expression of the p53 suppressor Mdm2, which is found in >50% of melanoma lesions. Here, we describe an organometallic glycogen synthase kinase 3beta (GSK3beta) inhibitor (DW1/2) as a potent activator of p53 and inducer of cell death in otherwise highly chemoresistant melanoma cells. Using RNA interference and pharmacologic approaches, we show that p53 is required for the cytotoxic effects of this organometallic inhibitor. The DW1/2 compound was barely able to induce cell death in melanoma cells with p53 mutations, further confirming the requirement for p53-WT in the cytotoxic effects of the GSK3beta inhibition. Mechanistic analysis of the p53-dependent cell death indicated an apoptotic mechanism involving depolarization of mitochondrial membrane potential, caspase cleavage, and elevated NOXA expression. The effect of p53 was not simply due to passive up-regulation of protein expression as adenoviral-mediated overexpression of p53 was not able to induce cell death. Treatment of melanoma cells with DW1/2 was instead found to decrease levels of Mdm2 and Mdm4. The importance of Mdm2 down-regulation in DW1/2-induced apoptosis was confirmed by treating the p53-WT cells with the p53/Mdm2 antagonist Nutlin-3. Taken together, our data provide a new strategy for the pharmacologic activation of p53 in melanoma, which may be a viable approach for overcoming apoptotic resistance in melanoma and offer new hope for rational melanoma therapy.


Proceedings of the National Academy of Sciences of the United States of America | 2007

Tumor cell-selective regulation of NOXA by c-MYC in response to proteasome inhibition

Mikhail A. Nikiforov; MaryBeth Riblett; Wen Hua Tang; Vladimir Gratchouck; Dazhong Zhuang; Yolanda Fernandez; Monique Verhaegen; Sooryanarayana Varambally; Arul M. Chinnaiyan; Andrzej J. Jakubowiak; Maria S. Soengas

The proteasome controls a plethora of survival factors in all mammalian cells analyzed to date. Therefore, it is puzzling that proteasome inhibitors such as bortezomib can display a preferential toxicity toward malignant cells. In fact, proteasome inhibitors have the salient feature of promoting a dramatic induction of the proapoptotic protein NOXA in a tumor cell-restricted manner. However, the molecular determinants that control this specific regulation of NOXA are unknown. Here, we show that the induction of NOXA by bortezomib is directly dependent on the oncogene c-MYC. This requirement for c-MYC was found in a variety of tumor cell types, in marked contrast with dispensable roles of p53, HIF-1α, and E2F-1 (classical proteasomal targets that can regulate NOXA mRNA under stress). Conserved MYC-binding sites identified at the NOXA promoter were validated by ChIP and reporter assays. Down-regulation of the endogenous levels of c-MYC abrogated the induction of NOXA in proteasome-defective tumor cells. Conversely, forced expression of c-MYC enabled normal cells to accumulate NOXA and subsequently activate cell death programs in response to proteasome blockage. c-MYC is itself a proteasomal target whose levels or function are invariably up-regulated during tumor progression. Our data provide an unexpected function of c-MYC in the control of the apoptotic machinery, and reveal a long sought-after oncogenic event conferring sensitivity to proteasome inhibition.


Cancer Cell | 2009

Targeted Activation of Innate Immunity for Therapeutic Induction of Autophagy and Apoptosis in Melanoma Cells

Damia Tormo; Agnieszka Checinska; Direna Alonso-Curbelo; Estela Cañón; Erica Riveiro-Falkenbach; Tonantzin G. Calvo; Lionel Larribere; Diego Megías; Francisca Mulero; Miguel A. Piris; Rupesh Dash; Paola M. Barral; José Luis Rodríguez-Peralto; Pablo L. Ortiz-Romero; Thomas Tüting; Paul B. Fisher; Maria S. Soengas

Inappropriate drug delivery, secondary toxicities, and persistent chemo- and immunoresistance have traditionally compromised treatment response in melanoma. Using cellular systems and genetically engineered mouse models, we show that melanoma cells retain an innate ability to recognize cytosolic double-stranded RNA (dsRNA) and mount persistent stress response programs able to block tumor growth, even in highly immunosuppressed backgrounds. The dsRNA mimic polyinosine-polycytidylic acid, coadministered with polyethyleneimine as carrier, was identified as an unanticipated inducer of autophagy downstream of an exacerbated endosomal maturation program. A concurrent activity of the dsRNA helicase MDA-5 driving the proapoptotic protein NOXA resulted in an efficient autodigestion of melanoma cells. These results reveal tractable links for therapeutic intervention among dsRNA helicases, endo/lysosomes, and apoptotic factors.


Oncogene | 2008

C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells

Dazhong Zhuang; S. Mannava; V. Grachtchouk; W. H. Tang; S. Patil; Joseph A. Wawrzyniak; A. E. Berman; T. J. Giordano; Edward V. Prochownik; Maria S. Soengas; Mikhail A. Nikiforov

Malignant melanomas often harbor activating mutations in BRAF (V600E) or, less frequently, in NRAS (Q61R). Intriguingly, the same mutations have been detected at higher incidences in benign nevi, which are largely composed of senescent melanocytes. Overexpression of BRAFV600E or NRASQ61R in human melanocytes in vitro has been shown to induce senescence, although via different mechanisms. How oncogene-induced senescence is overcome during melanoma progression remains unclear. Here, we report that in the majority of analysed BRAFV600E- or NRASQ61R-expressing melanoma cells, C-MYC depletion induced different yet overlapping sets of senescence phenotypes that are characteristic of normal melanocytes undergoing senescence due to overexpression of BRAFV600E or NRASQ61R, respectively. These senescence phenotypes were p16INK4A- or p53-independent, however, several of them were suppressed by genetic or pharmacological inhibition of BRAFV600E or phosphoinositide 3-kinase pathways, including rapamycin-mediated inhibition of mTOR-raptor in NRASQ61R-expressing melanoma cells. Reciprocally, overexpression of C-MYC in normal melanocytes suppressed BRAFV600E-induced senescence more efficiently than NRASQ61R-induced senescence, which agrees with the generally higher rates of activating mutations in BRAF than NRAS gene in human cutaneous melanomas. Our data suggest that one of the major functions of C-MYC overexpression in melanoma progression is to continuous suppress BRAFV600E- or NRASQ61R-dependent senescence programs.

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Erica Riveiro-Falkenbach

Complutense University of Madrid

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Scott W. Lowe

Memorial Sloan Kettering Cancer Center

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David Olmeda

Spanish National Research Council

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Pablo L. Ortiz-Romero

Complutense University of Madrid

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Mikhail A. Nikiforov

Roswell Park Cancer Institute

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Osvaldo Graña

Spanish National Research Council

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