Publications by authors named "Omid Tavana"

21 Publications

  • Page 1 of 1

AZD4320, A Dual Inhibitor of Bcl-2 and Bcl-x, Induces Tumor Regression in Hematologic Cancer Models without Dose-limiting Thrombocytopenia.

Clin Cancer Res 2020 Dec 28;26(24):6535-6549. Epub 2020 Sep 28.

DMPK, Oncology R&D, AstraZeneca, Boston, Massachusetts.

Purpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2-selective inhibitor, has had success in the clinic, another family member, Bcl-x, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-x inhibitor that broadens the therapeutic activity while minimizing Bcl-x-mediated thrombocytopenia.

Experimental Design: We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-x and assessed the activity against cell lines, patient samples, and models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time.

Results: We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-x, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2- and Bcl-x-dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2-selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-x-dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models.

Conclusions: AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-x inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0863DOI Listing
December 2020

Discovery of Proteolysis-Targeting Chimera Molecules that Selectively Degrade the IRAK3 Pseudokinase.

J Med Chem 2020 09 14;63(18):10460-10473. Epub 2020 Sep 14.

Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca, Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States.

We report the first disclosure of IRAK3 degraders in the scientific literature. Taking advantage of an opportune byproduct obtained during our efforts to identify IRAK4 inhibitors, we identified ready-to-use, selective IRAK3 ligands in our compound collection with the required properties for conversion into proteolysis-targeting chimera (PROTAC) degraders. This work culminated with the discovery of PROTAC , which we demonstrated to be a potent and selective degrader of IRAK3 after 16 h in THP1 cells. induced proteasome-dependent degradation of IRAK3 and required both CRBN and IRAK3 binding for activity. We conclude that PROTAC constitutes an excellent tool with which to interrogate the biology of IRAK3.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01125DOI Listing
September 2020

p53 modifications: exquisite decorations of the powerful guardian.

J Mol Cell Biol 2019 07;11(7):564-577

Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

The last 40 years have witnessed how p53 rose from a viral binding protein to a central factor in both stress responses and tumor suppression. The exquisite regulation of p53 functions is of vital importance for cell fate decisions. Among the multiple layers of mechanisms controlling p53 function, posttranslational modifications (PTMs) represent an efficient and precise way. Major p53 PTMs include phosphorylation, ubiquitination, acetylation, and methylation. Meanwhile, other PTMs like sumoylation, neddylation, O-GlcNAcylation, adenosine diphosphate (ADP)-ribosylation, hydroxylation, and β-hydroxybutyrylation are also shown to play various roles in p53 regulation. By independent action or interaction, PTMs affect p53 stability, conformation, localization, and binding partners. Deregulation of the PTM-related pathway is among the major causes of p53-associated developmental disorders or diseases, especially in cancers. This review focuses on the roles of different p53 modification types and shows how these modifications are orchestrated to produce various outcomes by modulating p53 activities or targeted to treat different diseases caused by p53 dysregulation.
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http://dx.doi.org/10.1093/jmcb/mjz060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736412PMC
July 2019

ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway.

Nat Cell Biol 2019 05 8;21(5):579-591. Epub 2019 Apr 8.

Institute for Cancer Genetics, and Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.

It is well established that ferroptosis is primarily controlled by glutathione peroxidase 4 (GPX4). Surprisingly, we observed that p53 activation modulates ferroptotic responses without apparent effects on GPX4 function. Instead, ALOX12 inactivation diminishes p53-mediated ferroptosis induced by reactive oxygen species stress and abrogates p53-dependent inhibition of tumour growth in xenograft models, suggesting that ALOX12 is critical for p53-mediated ferroptosis. The ALOX12 gene resides on human chromosome 17p13.1, a hotspot of monoallelic deletion in human cancers. Loss of one Alox12 allele is sufficient to accelerate tumorigenesis in Eμ-Myc lymphoma models. Moreover, ALOX12 missense mutations from human cancers abrogate its ability to oxygenate polyunsaturated fatty acids and to induce p53-mediated ferroptosis. Notably, ALOX12 is dispensable for ferroptosis induced by erastin or GPX4 inhibitors; conversely, ACSL4 is required for ferroptosis upon GPX4 inhibition but dispensable for p53-mediated ferroptosis. Thus, our study identifies an ALOX12-mediated, ACSL4-independent ferroptosis pathway that is critical for p53-dependent tumour suppression.
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http://dx.doi.org/10.1038/s41556-019-0305-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624840PMC
May 2019

The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11.

Cancer Res 2019 Apr 1;79(8):1913-1924. Epub 2019 Feb 1.

Institute for Cancer Genetics, Department of Pathology and Cell Biology, Columbia University, New York, New York.

Although cell-cycle arrest, senescence, and apoptosis are established mechanisms of tumor suppression, accumulating evidence reveals that ferroptosis, an iron-dependent, nonapoptotic form of cell death, represents a new regulatory pathway in suppressing tumor development. Ferroptosis is triggered by lipid peroxidation and is tightly regulated by SLC7A11, a key component of the cystine-glutamate antiporter. Although many studies demonstrate the importance of transcriptional regulation of SLC7A11 in ferroptotic responses, it remains largely unknown how the stability of SLC7A11 is controlled in human cancers. In this study, we utilized biochemial purification to identify the ubiquitin hydrolase OTUB1 as a key factor in modulating SLC7A11 stability. OTUB1 directly interacted with and stabilized SLC7A11; conversely, OTUB1 knockdown diminished SLC7A11 levels in cancer cells. OTUB1 was overexpressed in human cancers, and inactivation of OTUB1 destabilized SLC7A11 and led to growth suppression of tumor xenografts in mice, which was associated with reduced activation of ferroptosis. Notably, overexpression of the cancer stem cell marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; depletion of CD44 partially abrogated this interaction. CD44 expression suppressed ferroptosis in cancer cells in an OTUB1-dependent manner. Together, these results show that OTUB1 plays an essential role in controlling the stability of SLC7A11 and the CD44-mediated effects on ferroptosis in human cancers. SIGNIFICANCE: This study identifies OTUB1 as a key regulator of ferroptosis and implicates it as a potential target in cancer therapy..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467774PMC
April 2019

ARF-NRF2: A new checkpoint for oxidative stress responses?

Mol Cell Oncol 2018 6;5(3):e1432256. Epub 2018 Feb 6.

Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, 1130 St. Nicholas Avenue, New York, New York.

NRF2 (nuclear factor erythroid 2-related factor 2) is a transcription factor which plays a major role in oxidative stress responses by regulating antioxidant gene expression. We have recently identified the ARF tumor suppressor as a key regulator of NRF2. ARF can significantly inhibit NRF2 transcriptional activities, and the ARF-NRF2 interaction may function as a novel checkpoint for oxidative stress responses.
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http://dx.doi.org/10.1080/23723556.2018.1432256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149754PMC
February 2018

Targeting HAUSP in both p53 wildtype and p53-mutant tumors.

Cell Cycle 2018 15;17(7):823-828. Epub 2018 May 15.

a Institute for Cancer Genetics , Department of Pathology and Cell Biology , New York , NY , USA.

Inhibition of Mdm2 function is a validated approach to restore p53 activity for cancer therapy; nevertheless, inhibitors of Mdm2 such as Nutlin-3 have certain limitations, suggesting that additional targets in this pathway need to be further elucidated. Our finding that the Herpesvirus-Associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with the p53/Mdm2 protein complex, was one of the first examples that deubiquitinases (DUBs) exhibit a specific role in regulating protein stability. Here, we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53-dependent apoptosis in human cancer cells. Notably, HAUSP can also target the N-Myc oncoprotein in a p53-independent manner. Moreover, newly synthesized HAUSP inhibitors are more potent than the commercially available inhibitors to suppress N-Myc activities in p53 mutant cells for growth suppression. Taken together, our study demonstrates the utility of HAUSP inhibitors to target cancers in both a p53-depdentent and -independent manner.
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http://dx.doi.org/10.1080/15384101.2018.1456293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056219PMC
December 2019

Peli1 Modulates the Subcellular Localization and Activity of Mdmx.

Cancer Res 2018 06 9;78(11):2897-2910. Epub 2018 Mar 9.

Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York.

Mdm2 and Mdmx, both major repressors of p53 in human cancers, are predominantly localized to the nucleus and cytoplasm, respectively. The mechanism by which subcellular localization of Mdmx is regulated remains unclear. In this study, we identify the E3 ligase Peli1 as a major binding partner and regulator of Mdmx in human cells. Peli1 bound Mdmx and and promoted high levels of ubiquitination of Mdmx. Peli1-mediated ubiquitination was degradation-independent, promoting cytoplasmic localization of Mdmx, which in turn resulted in p53 activation. Consistent with this, knockdown or knockout Peli1 in human cancer cells induced nuclear localization of Mdmx and suppressed p53 activity. Myc-induced tumorigenesis was accelerated in Peli1-null mice and associated with downregulation of p53 function. Clinical samples of human cutaneous melanoma had decreased Peli1 expression, which was associated with poor overall survival. Together, these results demonstrate that Peli1 acts as a critical factor for the Mdmx-p53 axis by modulating the subcellular localization and activity of Mdmx, thus revealing a novel mechanism of Mdmx deregulation in human cancers. Peli1-mediated regulation of Mdmx, a major inhibitor of p53, provides critical insight into activation of p53 function in human cancers. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-3531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984691PMC
June 2018

Independent functions of DNMT1 and USP7 at replication foci.

Epigenetics Chromatin 2018 02 27;11(1). Epub 2018 Feb 27.

Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, 701 W. 168th St, New York, NY, 10032, USA.

Background: It has been reported that USP7 (ubiquitin-specific protease 7) prevents ubiquitylation and degradation of DNA methyltransferase 1 (DNMT1) by direct binding of USP7 to the glycine-lysine (GK) repeats that join the N-terminal regulatory domain of DNMT1 to the C-terminal methyltransferase domain. The USP7-DNMT1 interaction was reported to be mediated by acetylation of lysine residues within the (GK) repeats.

Results: We found that DNMT1 is present at normal levels in mouse and human cells that contain undetectable levels of USP7. Substitution of the (GK) repeats by (GQ) repeats prevents lysine acetylation but does not affect the stability of DNMT1 or the ability of the mutant protein to restore genomic methylation levels when expressed in Dnmt1-null ES cells. Furthermore, both USP7 and PCNA are recruited to sites of DNA replication independently of the presence of DNMT1, and there is no evidence that DNMT1 is degraded in cycling cells after S phase.

Conclusions: Multiple lines of evidence indicate that homeostasis of DNMT1 in somatic cells is controlled primarily at the level of transcription and that interaction of USP7 with the (GK) repeats of DNMT1 is unlikely to play a major role in the stabilization of DNMT1 protein.
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http://dx.doi.org/10.1186/s13072-018-0179-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828336PMC
February 2018

NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression.

Mol Cell 2017 Oct;68(1):224-232.e4

Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address:

Although ARF can suppress tumor growth by activating p53 function, the mechanisms by which it suppresses tumor growth independently of p53 are not well understood. Here, we identified ARF as a key regulator of nuclear factor E2-related factor 2 (NRF2) through complex purification. ARF inhibits the ability of NRF2 to transcriptionally activate its target genes, including SLC7A11, a component of the cystine/glutamate antiporter that regulates reactive oxygen species (ROS)-induced ferroptosis. As a consequence, ARF expression sensitizes cells to ferroptosis in a p53-independent manner while ARF depletion induces NRF2 activation and promotes cancer cell survival in response to oxidative stress. Moreover, the ability of ARF to induce p53-independent tumor growth suppression in mouse xenograft models is significantly abrogated upon NRF2 overexpression. These results demonstrate that NRF2 is a major target of p53-independent tumor suppression by ARF and also suggest that the ARF-NRF2 interaction acts as a new checkpoint for oxidative stress responses.
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http://dx.doi.org/10.1016/j.molcel.2017.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683418PMC
October 2017

The "readers" of unacetylated p53 represent a new class of acidic domain proteins.

Nucleus 2017 Jul 13;8(4):360-369. Epub 2017 Apr 13.

a Institute for Cancer Genetics, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons , Columbia University , New York , NY , USA.

Acetylation of non-histone proteins plays important roles in regulating protein functions but the mechanisms of action are poorly understood. Our recent study uncovered a previously unknown mechanism by which C-terminal domain (CTD) acetylation of p53 serves as a "switch" to determine the interaction between a unique group of acidic domain-containing proteins and p53, as well as revealed that acidic domains may act as a novel class of "readers" for unacetylated p53. However, the properties of acidic domain "readers" are not well elucidated yet. Here, we identified that the charge effect between acidic domain "readers" and the p53 CTD is necessary for their interaction. Both the length and the amino acid composition of a given acidic domain contributed to its ability to recognize the p53 CTD. Finally, we summarized the characteristic features of our identified acidic domains, which would distinguish this kind of "readers" from other types of acidic amino acid-containing domains.
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http://dx.doi.org/10.1080/19491034.2017.1313939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597292PMC
July 2017

Modulation of the p53/MDM2 interplay by HAUSP inhibitors.

Authors:
Omid Tavana Wei Gu

J Mol Cell Biol 2017 02;9(1):45-52

College of Physicians and Surgeons, Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.

It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase activity, as well as the protein-protein interaction between p53 and MDM2, is the major focus for this regulation, emerging evidence suggests that the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7) plays a critical role. Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes. In this review, we discuss the advances of this dynamic pathway and the contributions of positive and negative regulators affecting HAUSP activity. We also highlight the roles of HAUSP in cancer justifying the production of the first generation of HAUSP inhibitors.
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http://dx.doi.org/10.1093/jmcb/mjw049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310345PMC
February 2017

HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma.

Nat Med 2016 10 12;22(10):1180-1186. Epub 2016 Sep 12.

Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York, USA.

The MYCN proto-oncogene is amplified in a number of advanced-stage human tumors, such as neuroblastomas. Similar to other members of the MYC family of oncoproteins, MYCN (also known as N-Myc) is a transcription factor, and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation. Although numerous studies have demonstrated that N-Myc is a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here we have identified ubiquitin-specific protease 7 (USP7; also known as HAUSP) as a regulator of N-Myc function in neuroblastoma. HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc. Conversely, RNA interference (RNAi)-mediated knockdown of USP7 in neuroblastoma cancer cell lines, or genetic ablation of Usp7 in the mouse brain, destabilizes N-Myc, which leads to inhibition of N-Myc function. Notably, HAUSP is more abundant in patients with neuroblastoma who have poorer prognosis, and HAUSP expression substantially correlates with N-Myc transcriptional activity. Furthermore, small-molecule inhibitors of HAUSP's deubiquitinase activity markedly suppress the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models. Taken together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors.
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http://dx.doi.org/10.1038/nm.4180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091299PMC
October 2016

Controlling ARF stability: new players added to the team.

Cell Cycle 2014 13;13(4):497-8. Epub 2014 Jan 13.

Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University; New York, NY USA.

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http://dx.doi.org/10.4161/cc.27786DOI Listing
April 2015

Ku70 functions in addition to nonhomologous end joining in pancreatic β-cells: a connection to β-catenin regulation.

Diabetes 2013 Jul 8;62(7):2429-38. Epub 2013 Mar 8.

Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

The genesis of β-cells predominantly occurs through self-replication; therefore, understanding the regulation of cell proliferation is essential. We previously showed that the lack of nonhomologous end joining (NHEJ) DNA repair factor ligase IV leads to an accumulation of DNA damage that permanently halts β-cell proliferation and dramatically decreases insulin production, causing overt diabetes in a hypomorphic p53(R172P) background. In the present study, to further delineate the function of NHEJ, we analyzed mice deficient for another key NHEJ factor, Ku70, to discover the effect of cellular responses to DNA damage in pancreatic β-cells on cellular proliferation and glucose homeostasis. Analysis of Ku70(-/-) pancreatic β-cells revealed an accumulation of DNA damage and activation of p53-dependent cellular senescence similar to the results found in our earlier ligase IV deficiency study. To our surprise, Ku70(-/-) mice had significantly increased β-cell proliferation and islet expansion, heightened insulin levels, and decreased glycemia. This augmented β-cell proliferation was accompanied by an increased β-catenin level, which we propose to be responsible for this phenotype. This study highlights Ku70 as an important player not only in maintaining genomic stability through NHEJ-dependent functions, but also in regulating pancreatic β-cell proliferation, a novel NHEJ-independent function.
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http://dx.doi.org/10.2337/db12-1218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712041PMC
July 2013

The Hunger Games: p53 regulates metabolism upon serine starvation.

Authors:
Omid Tavana Wei Gu

Cell Metab 2013 Feb;17(2):159-61

Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.

Cancer cells reprogram their metabolism to support a high proliferative rate. A new study shows that, upon serine starvation, the tumor suppressor p53 activates p21 to shift metabolic flux from purine biosynthesis to glutathione production, which enhances cellular proliferation and viability by combating ROS (Maddocks et al., 2013).
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http://dx.doi.org/10.1016/j.cmet.2013.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634368PMC
February 2013

p53 and DNA methylation suppress the TRAIN to cell death.

Authors:
Omid Tavana Wei Gu

Cell Cycle 2013 Jan 19;12(1):9-10. Epub 2012 Dec 19.

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http://dx.doi.org/10.4161/cc.23324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570522PMC
January 2013

p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer.

Cancer Cell 2012 Jun;21(6):793-806

Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Studies on the role of TP53 mutation in breast cancer response to chemotherapy are conflicting. Here, we show that, contrary to dogma, MMTV-Wnt1 mammary tumors with mutant p53 exhibited a superior clinical response compared to tumors with wild-type p53. Doxorubicin-treated p53 mutant tumors failed to arrest proliferation, leading to abnormal mitoses and cell death, whereas p53 wild-type tumors arrested, avoiding mitotic catastrophe. Senescent tumor cells persisted, secreting senescence-associated cytokines exhibiting autocrine/paracrine activity and mitogenic potential. Wild-type p53 still mediated arrest and inhibited drug response even in the context of heterozygous p53 point mutations or absence of p21. Thus, we show that wild-type p53 activity hinders chemotherapy response and demonstrate the need to reassess the paradigm for p53 in cancer therapy.
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http://dx.doi.org/10.1016/j.ccr.2012.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376352PMC
June 2012

Too many breaks (brakes): pancreatic β-cell senescence leads to diabetes.

Cell Cycle 2011 Aug 1;10(15):2471-84. Epub 2011 Aug 1.

Department of Immunology, The Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Pancreatic β-cells regulate glucose homeostasis by secreting insulin in response to metabolic demands. The generation of these adult endocrine cells predominantly occurs through self-replication rather than through differentiation from their stem-cell progenitors; therefore, regulating cellular division through the cell cycle machinery is an essential component of this process. Arrest of the pancreatic β-cell cycle, which abolishes this replication capability, results in an inability to meet the metabolic demand for insulin, disrupting glucose homeostasis collectively driving type 2 diabetes mellitus-the most common metabolic disease worldwide. Therefore, the purpose of this review is to highlight how upstream cell cycle transcriptional regulators, direct cell cycle modulators, and external stress factors such as DNA damage and genomic instability, influence β-cell replication. We specifically highlight and compare recent animal models created to understand β-cell hyperplasia and hypoplasia as well as offer some insight into potential diabetic therapies.
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http://dx.doi.org/10.4161/cc.10.15.16741DOI Listing
August 2011

Absence of p53-dependent apoptosis leads to UV radiation hypersensitivity, enhanced immunosuppression and cellular senescence.

Cell Cycle 2010 Aug 16;9(16):3328-36. Epub 2010 Aug 16.

Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Genotoxic stress triggers the p53 tumor suppressor network to activate cellular responses that lead to cell cycle arrest, DNA repair, apoptosis or senescence. This network functions mainly through transactivation of different downstream targets, including cell cycle inhibitor p21, which is required for short-term cell cycle arrest or long-term cellular senescence, or proapoptotic genes such as p53 upregulated modulator of apoptosis (PUMA) and Noxa. However, the mechanism that switches from cell cycle arrest to apoptosis is still unknown. In this study, we found that mice harboring a hypomorphic mutant p53, R172P, a mutation that abrogates p53-mediated apoptosis while keeping cell cycle control mostly intact, are more susceptible to ultraviolet-B (UVB)-induced skin damage, inflammation and immunosuppression than wild-type mice. p53(R172P) embryonic fibroblasts (MEFs) are hypersensitive to UVB and prematurely senesce after UVB exposure, in stark contrast to wild-type MEFs, which undergo apoptosis. However, these mutant cells are able to repair UV-induced DNA lesions, indicating that the UV hypersensitive phenotype results from the subsequent damage response. Mutant MEFs show an induction of p53 and p21 after UVR, while wild-type MEFs additionally induce PUMA and Noxa. Importantly, p53(R172P) MEFs failed to downregulate anti-apoptotic protein Bcl-2, which has been shown to play an important role in p53-dependent apoptosis. Taken together, these data demonstrate that in the absence of p53-mediated apoptosis, cells undergo cellular senescence to prevent genomic instability. Our results also indicate that p53-dependent apoptosis may play an active role in balancing cellular growth.
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http://dx.doi.org/10.4161/cc.9.16.12688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041166PMC
August 2010

Absence of p53-dependent apoptosis combined with nonhomologous end-joining deficiency leads to a severe diabetic phenotype in mice.

Diabetes 2010 Jan 15;59(1):135-42. Epub 2009 Oct 15.

Department of Immunology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA.

Objective: Regulation of pancreatic beta-cell mass is essential to preserve sufficient insulin levels for the maintenance of glucose homeostasis. Previously, we reported that DNA double-strand breaks (DSBs) resulting from nonhomologous end-joining (NHEJ) deficiency induce apoptosis and, when combined with p53 deficiency, progressed rapidly into lymphomagenesis in mice. Combination of NHEJ deficiency with a hypomorphic mutation, p53R172P, leads to the abrogation of apoptosis, upregulation of p21, and senescence in precursor lymphocytes. This was sufficient to prevent tumorigenesis. However, these mutant mice succumb to severe diabetes and die at an early age. The aim of this study was to determine the pathogenesis of diabetes in these mutant mice.

Research Design And Methods: We analyzed the morphology of the pancreatic islets and the function, proliferation rate, and senescence of beta-cells. We also profiled DNA damage and p53 and p21 expression in the pancreas.

Results: NHEJ-p53R172P mutant mice succumb to diabetes at 3-5 months of age. These mice show a progressive decrease in pancreatic islet mass that is independent of apoptosis and innate immunity. We observed an accumulation of DNA damage, accompanied with increased levels of p53 and p21, a significant decrease in beta-cell proliferation, and cellular senescence in the mutant pancreatic islets.

Conclusions: Combined DSBs with an absence of p53-dependent apoptosis activate p53-dependent senescence, which leads to a diminished beta-cell self-replication, massive depletion of the pancreatic islets, and severe diabetes. This is a model that connects impaired DNA repair and accumulative DNA damage, a common phenotype in aging individuals, to the onset of diabetes.
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http://dx.doi.org/10.2337/db09-0792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797914PMC
January 2010