MODIFICATIONS MATTER IN MCL1 TURNOVER AND CELL VIABILITY
Ruth W Craig, Professor
Pharmacology And Toxicologydartmouth College
Grant 5R01CA057359-16 from National Cancer Institute, IRG: ZRG1
Abstract: MCL1 is an antiapoptotic BCL2 family member that acts at a pivotal point in the apoptotic cascade and that is dynamically regulated to control viability at critical stages in cell proliferation and differentiation. Alterations that affect its normal regulated expression pattern can contribute to cancer, as seen in MCL1 transgenic mice and a variety of human malignancies. Our work progressed from the identification of MCL1 to studies of its effects and regulation, and is now unraveling a complex web of post-translational modifications. Our long-term goal is to delineate the mechanisms that regulate MCL1, and to understand how its dysregulation contributes to and thus might be targeted in cancer. The working hypothesis for our ongoing work is that MCL1 is subject to post-translational regulation through both exogenous signals and events linked to the cell cycle. Signaling-related regulation is illustrated by the ERK-inducible phosphorylation that slows the rapid turnover of the MCL1 protein. Cell cycle-related regulation is illustrated by the ERK-independent phosphorylation/band shift in G2/M phase which, along with an intriguing modification at the N-terminus (truncation), influences degradation as cells complete the cycle. AIM I will determine how signaling pathway-induced phosphorylation influences MCL1 stabilization/destabilization and thus its expression level and effects. This may maintain MCL1 expression in response to signals for viability- enhancement, or allow turnover for the induction of apoptosis. AIM II will dissect how the G2/M- phosphorylation/band shift and the N-terminal truncation control MCL1 degradation in cells traversing from one cycle to the next. This may aid in resetting MCL1 expression levels, and thus allow a fresh opportunity for regulation in newly divided cells. Our recent findings show that as transgenic mice grow older they demonstrate constitutive expression of MCL1 at levels normally seen upon stimulation. This is associated with increased resistance to cell death and occurs before tumors develop. It may thus allow the accumulation of further tumorigenic changes. Accordingly, AIM III will produce transgenic mice exhibiting expression of MCL1 at these increased levels, and/or containing forms of MCL1 that are less readily degraded through signaling- or cycle-related mechanisms. Elucidation of the multiple modes of MCL1 regulation, and the role of dysregulation in tumorigenesis, will suggest mechanisms that can be exploited and provide transgenic systems that can be utilized to target this BCL2 family member for the promotion of apoptosis at early as well as later stages of cancer
Keywords: B cell lymphoma, BCL2 gene /protein, apoptosis, carcinogenesis, genetic regulation, posttranslational modification cell cycle, cell differentiation, gene expression, phosphoprotein, phosphorylation genetically modified animal, laboratory mouse
Project start date: 1992-06-01
Project end date: 2011-07-31
Sponsored Links Lab Supply Mall http://www.labsupplymall.com
FORMS AND FUNCTION OF MCL1, A BCL2-RELATED GENE PRODUCT
Ruth W Craig, Professor
Dartmouth College Office Of Sponsored Projects Hanover, Nh 03755
Grant 5R01CA057359-08 from National Cancer Institute, IRG: PTHB
Abstract: We discovered mcl-1, a member of the bcl-2 family, by screening for genes that increase in expression early in the differentiation of ML-1 human myeloblastic leukemia cells. Our further studies have revealed mcl-1 to be similar to bcl-2 in some characteristics and different in others For example, mcl-1 can enhance cell viability under some apoptosis-inducing conditions, although it may have effects less pronounced than those of bcl-2. Similarly, mcl-1 is prominent in mitochondria and exhibits a distribution that overlaps with, but is not identical to, that of bcl-2. Finally, mcl-1 co-immunoprecipitates with a 22 KD protein, as does bcl-2. The mcl-1 protein exists as three species, visualized as three closely spaced bands on blots. A shift in the relative abundance of these bands occurs during ML-1 cell differentiation. In addition, certain of these bands are phosphorylated, phosphorylation occurring on serine. We now plan to determine how the expression and phosphorylation of the different species of mcl-1 relates to function. In Aim I, we will complete the characterization of the effects of mcl-1 on cell viability, determining whether mcl-1 can inhibit cell death under a broad range of conditions as can bcl-2. In Aim II, we will identify the 22 KD protein and further characterize its interaction with mcl-1. In Aim III, we will identify the structural differences that distinguish the different species of the mcl-1 protein; we will determine, for example, how phosphorylation contributes to the appearance of these different species. In Aim IV, we will determine how phosphorylation (and any other modifications of mcl-1 discovered in Aim III) influence both the effect of mcl-1 on cell viability and the interaction of mcl-1 with the 22 KD protein. In Aim V, we will determine when (e.g., how early) in the death process mcl-1 must be expressed in order to exert its effects on viability. Taken together, these studies on mcl-1 will contribute to an emerging understanding of how genes in the bcl-2 family are regulated, and how these genes, in turn, regulate cell viability versus death.
Keywords: BCL2 gene /protein, acute myelogenous leukemia, cell differentiation, gene expression, genetic regulation, protein structure, cell cycle, cis platinum compound, cytotoxicity, etoposide, growth factor, phosphorylation, posttranslational modification, programmed cell death, staurosporine, high performance liquid chromatography, nucleic acid sequence, site directed mutagenesis, transfection
Project start date: 1992-06-01
Project end date: 2000-03-31
5R01CA057359-08 (1999): $322174
5R01CA057359-07 (1998): $308232
5R01CA057359-06 (1997): $294887
PROTEIN ENCODED BY MCL-1 LIKE OR UNLIKE BCL-2?
Ruth W Craig, Professor
Dartmouth College Office Of Sponsored Projects Hanover, Nh 03755
Grant 5R01CA057359-03 from National Cancer Institute, IRG: PTHB
Abstract: Our long-term objective is to understand the molecular events that underlie the induction of differentiation in ML-1 human myeloblastic leukemia cells. We have identified a gene that increases in expression early in induction with 12-0-tetradecanoylphorbol-13-acetate (TPA). We have designated this gene mcl-1, based on its isolation from maturing myeloid ML-1 cell leukemia. The increase in mcl-1 mRNA occurs within one to three hours, preceding maturation to monocyte/macrophages at one to three days. We found mcl-1 to exhibit significant homology to bcl-2, a gene that plays an as-yet poorly understood role in t(14;18)B-cell lymphomas. mcl-1 is the first example of a cellular gene with significant homology to bcl-2. We now propose to study the mcl-1-encoded protein, exploring its possible site(s) of action and role(s) in cell proliferation, differentiation, and viability. We will study the behavior of the mcl-1 protein in cell-free systems (Aim I), determining whether it is processed by microsomal membranes (via its putative signal sequence) or might associate with isolated mitochondria (via the potential membrane spanning region with homology to bcl-2). We will prepare monoclonal and polyclonal antibodies (Aim II) for use in studying the mcl-1 protein in intact cells (Aim III) Using results from Aim I as a guide, we will assess the intracellular localization of mcl-1 (Aim IIIA). We will also determine how expression of the mcl-1 protein relates to hematopoietic cell lineage, maturation stage, and proliferation status (Aim IIIB). Finally, using electroporation, we will test for effects of mcl-1 on cell viability or mitochondrial function (Aim IIIC). It will be interesting to compare mcl-1 to bcl-2, which localizes to mitochondria, is expressed in immature cells of the lymphoid lineage, and can block apoptosis. mcl-1, bcl-2, and a related viral gene BHRF-1, may define a family of genes different from other known families including oncogenes. The studies proposed here should yield information basic to elucidating the function of mcl-1; they may also advance us towards an integrated understanding of this emerging gene family.
Keywords: acute myelogenous leukemia, cell differentiation, gene expression, membrane protein, mitochondrial membrane, myeloid stem cell, nucleic acid structure, bone marrow, hematopoietic stem cell, mitochondria, programmed cell death, cell free system, electroporation, genetic translation, human tissue, immunoprecipitation, laboratory mouse, monoclonal antibody, phorbol, radiotracer, western blotting
Project start date: 1992-06-01
Project end date: 1995-05-31
5R01CA057359-03 (1994): $168275
MODIFICATIONS MATTER IN MCL1 TURNOVER AND CELL VIABILITY
Ruth W Craig, Professor
Dartmouth College Office Of Sponsored Projects Hanover, Nh 03755
Grant 5R01CA057359-15 from National Cancer Institute, IRG: ZRG1
Abstract: MCL1 is an antiapoptotic BCL2 family member that acts at a pivotal point in the apoptotic cascade and that is dynamically regulated to control viability at critical stages in cell proliferation and differentiation. Alterations that affect its normal regulated expression pattern can contribute to cancer, as seen in MCL1 transgenic mice and a variety of human malignancies. Our work progressed from the identification of MCL1 to studies of its effects and regulation, and is now unraveling a complex web of post-translational modifications. Our long-term goal is to delineate the mechanisms that regulate MCL1, and to understand how its dysregulation contributes to and thus might be targeted in cancer. The working hypothesis for our ongoing work is that MCL1 is subject to post-translational regulation through both exogenous signals and events linked to the cell cycle. Signaling-related regulation is illustrated by the ERK-inducible phosphorylation that slows the rapid turnover of the MCL1 protein. Cell cycle-related regulation is illustrated by the ERK-independent phosphorylation/band shift in G2/M phase which, along with an intriguing modification at the N-terminus (truncation), influences degradation as cells complete the cycle. AIM I will determine how signaling pathway-induced phosphorylation influences MCL1 stabilization/destabilization and thus its expression level and effects. This may maintain MCL1 expression in response to signals for viability- enhancement, or allow turnover for the induction of apoptosis. AIM II will dissect how the G2/M- phosphorylation/band shift and the N-terminal truncation control MCL1 degradation in cells traversing from one cycle to the next. This may aid in resetting MCL1 expression levels, and thus allow a fresh opportunity for regulation in newly divided cells. Our recent findings show that as transgenic mice grow older they demonstrate constitutive expression of MCL1 at levels normally seen upon stimulation. This is associated with increased resistance to cell death and occurs before tumors develop. It may thus allow the accumulation of further tumorigenic changes. Accordingly, AIM III will produce transgenic mice exhibiting expression of MCL1 at these increased levels, and/or containing forms of MCL1 that are less readily degraded through signaling- or cycle-related mechanisms. Elucidation of the multiple modes of MCL1 regulation, and the role of dysregulation in tumorigenesis, will suggest mechanisms that can be exploited and provide transgenic systems that can be utilized to target this BCL2 family member for the promotion of apoptosis at early as well as later stages of cancer.
Keywords: B cell lymphoma, BCL2 gene /protein, apoptosis, carcinogenesis, genetic regulation, posttranslational modification, cell cycle, cell differentiation, gene expression, phosphoprotein, phosphorylation, genetically modified animal, laboratory mouse
Project start date: 1992-06-01
Project end date: 2011-07-31
5R01CA057359-15 (2007): $308120
CONTROL OF THE SURVIVAL REGULATOR MCL1 AND TUMORIGENESIS
Ruth W Craig, Professor
Dartmouth College Office Of Sponsored Projects Hanover, Nh 03755
Grant 5R01CA057359-13 from National Cancer Institute, IRG: HEM
Abstract: Adapted from investigator s ) MCL1 is an anti-apoptotic member of the BCL-2 family that can be rapidly upregulated and a PEST protein that can be rapidly turned over. MCL1 is normally expressed at specific stages of differentiation and in response to specific stimuli. MCL1 transgenic mice have a high probability of developing massive lymph node hyperplasia with long latency leading to malignant lymphoma with high probability. Preliminary data indicate that MCL1 is subject to three post-translational modifications including two differing types of phosphorylation seen in viable versus apoptosing cells. The MCL1 phosphorylation seen in viable cells is not associated with a change in electrophoretic mobility; in contrast, the MCL1 phosphorylation seen in cells exposed to certain apoptosis-inducing agents is associated with a distinct change in mobility. MCL1 also undergoes a separate third modification that involves the loss of a segment at the N-terminus. This proposal focuses on these three modifications and on their impact on the anti-apoptotic activity of MCL1 and on the tumorigenesis seen in the MCL1 transgenic mice. BCL2 phosphorylation has been variously reported to enhance or to inhibit its anti-apoptotic function, and the fact that MCL1 phosphorylation differs in viable versus apoptosing cells may lend insight into this issue. Given this background, the investigator plans to determine how specific post-translation modifications (i.e., phosphorylation; n-terminal modifications) affects turnover and the anti-apoptotic activity of MCL1. These studies will be complemented by in vivo assessment of the importance of these modifications, utilizing the transgenic system, which the investigator has developed.
Keywords: B cell lymphoma, BCL2 gene /protein, apoptosis, carcinogenesis, genetic regulation, posttranslational modification, cell cycle, cell differentiation, gene expression, phosphoprotein, phosphorylation, genetically modified animal, laboratory mouse
Project start date: 1992-06-01
Project end date: 2006-07-31
5R01CA057359-13 (2004): $321975
5R01CA057359-12 (2003): $321975
5R01CA057359-11 (2002): $385575
5R01CA057359-10 (2001): $385575
FORMS AND FUNCTION OF MCL1, A BCL2-RELATED GENE PRODUCT
Ruth W Craig, Professor
Dartmouth College Office Of Sponsored Projects Hanover, Nh 03755
Grant 5R01CA057359-05 from National Cancer Institute, IRG: PTHB
Project start date: 1992-06-01
Project end date: 2000-03-31
5R01CA057359-05 (1996): $282115
Grants awarded to Ruth W Craig
PROTEIN ENCODED BY MCL-1 LIKE OR UNLIKE BCL-2?
Ruth W Craig, Professor
Dartmouth College
office Of Sponsored Projects
hanover, Nh 03755
Grant 7R01CA057359-02 from National Cancer Institute, IRG: PTHB
Abstract: Our long-term objective is to understand the molecular events that underlie the induction of differentiation in ML-1 human myeloblastic leukemia cells. We have identified a gene that increases in expression early in induction with 12-0-tetradecanoylphorbol-13-acetate (TPA). We have designated this gene mcl-1, based on its isolation from maturing myeloid ML-1 cell leukemia. The increase in mcl-1 mRNA occurs within one to three hours, preceding maturation to monocyte/macrophages at one to three days. We found mcl-1 to exhibit significant homology to bcl-2, a gene that plays an as-yet poorly understood role in t(14;18)B-cell lymphomas. mcl-1 is the first example of a cellular gene with significant homology to bcl-2. We now propose to study the mcl-1-encoded protein, exploring its possible site(s) of action and role(s) in cell proliferation, differentiation, and viability. We will study the behavior of the mcl-1 protein in cell-free systems (Aim I), determining whether it is processed by microsomal membranes (via its putative signal sequence) or might associate with isolated mitochondria (via the potential membrane spanning region with homology to bcl-2). We will prepare monoclonal and polyclonal antibodies (Aim II) for use in studying the mcl-1 protein in intact cells (Aim III) Using results from Aim I as a guide, we will assess the intracellular localization of mcl-1 (Aim IIIA). We will also determine how expression of the mcl-1 protein relates to hematopoietic cell lineage, maturation stage, and proliferation status (Aim IIIB). Finally, using electroporation, we will test for effects of mcl-1 on cell viability or mitochondrial function (Aim IIIC). It will be interesting to compare mcl-1 to bcl-2, which localizes to mitochondria, is expressed in immature cells of the lymphoid lineage, and can block apoptosis. mcl-1, bcl-2, and a related viral gene BHRF-1, may define a family of genes different from other known families including oncogenes. The studies proposed here should yield information basic to elucidating the function of mcl-1; they may also advance us towards an integrated understanding of this emerging gene family
Keywords: acute myelogenous leukemia, cell differentiation, gene expression, membrane protein, mitochondrial membrane, myeloid stem cell, nucleic acid structure bone marrow, hematopoietic stem cell, mitochondria, programmed cell death cell free system, electroporation, genetic translation, human tissue, immunoprecipitation, laboratory mouse, monoclonal antibody, phorbol, radiotracer, western blotting
Project start date: 1992-06-01
Project end date: 1995-05-31
7R01CA057359-02 (1993): $163925
MODIFICATIONS MATTER IN MCL1 TURNOVER AND CELL VIABILITY
Ruth W Craig, Professor
Pharmacology And Toxicologydartmouth College
Grant 5R01CA057359-16 from National Cancer Institute, IRG: ZRG1
Abstract: MCL1 is an antiapoptotic BCL2 family member that acts at a pivotal point in the apoptotic cascade and that is dynamically regulated to control viability at critical stages in cell proliferation and differentiation. Alterations that affect its normal regulated expression pattern can contribute to cancer, as seen in MCL1 transgenic mice and a variety of human malignancies. Our work progressed from the identification of MCL1 to studies of its effects and regulation, and is now unraveling a complex web of post-translational modifications. Our long-term goal is to delineate the mechanisms that regulate MCL1, and to understand how its dysregulation contributes to and thus might be targeted in cancer. The working hypothesis for our ongoing work is that MCL1 is subject to post-translational regulation through both exogenous signals and events linked to the cell cycle. Signaling-related regulation is illustrated by the ERK-inducible phosphorylation that slows the rapid turnover of the MCL1 protein. Cell cycle-related regulation is illustrated by the ERK-independent phosphorylation/band shift in G2/M phase which, along with an intriguing modification at the N-terminus (truncation), influences degradation as cells complete the cycle. AIM I will determine how signaling pathway-induced phosphorylation influences MCL1 stabilization/destabilization and thus its expression level and effects. This may maintain MCL1 expression in response to signals for viability- enhancement, or allow turnover for the induction of apoptosis. AIM II will dissect how the G2/M- phosphorylation/band shift and the N-terminal truncation control MCL1 degradation in cells traversing from one cycle to the next. This may aid in resetting MCL1 expression levels, and thus allow a fresh opportunity for regulation in newly divided cells. Our recent findings show that as transgenic mice grow older they demonstrate constitutive expression of MCL1 at levels normally seen upon stimulation. This is associated with increased resistance to cell death and occurs before tumors develop. It may thus allow the accumulation of further tumorigenic changes. Accordingly, AIM III will produce transgenic mice exhibiting expression of MCL1 at these increased levels, and/or containing forms of MCL1 that are less readily degraded through signaling- or cycle-related mechanisms. Elucidation of the multiple modes of MCL1 regulation, and the role of dysregulation in tumorigenesis, will suggest mechanisms that can be exploited and provide transgenic systems that can be utilized to target this BCL2 family member for the promotion of apoptosis at early as well as later stages of cancer
Keywords: B cell lymphoma, BCL2 gene /protein, apoptosis, carcinogenesis, genetic regulation, posttranslational modification cell cycle, cell differentiation, gene expression, phosphoprotein, phosphorylation genetically modified animal, laboratory mouse
Project start date: 1992-06-01
Project end date: 2011-07-31
2R01CA057359-14A2 (2006): $317322
CONTROL OF THE SURVIVAL REGULATOR MCL1 AND TUMORIGENESIS
Ruth W Craig, Professor
Pharmacology And Toxicologydartmouth College
office Of Sponsored Projects
hanover, Nh 03755
Grant 2R01CA057359-09 from National Cancer Institute, IRG: HEM
Abstract: MCL1 is an anti-apoptotic member of the BCL-2 family that can be rapidly upregulated and a PEST protein that can be rapidly turned over. MCL1 is normally expressed at specific stages of differentiation and in response to specific stimuli. MCL1 transgenic mice have a high probability of developing massive lymph node hyperplasia with long latency leading to malignant lymphoma with high probability. Preliminary data indicate that MCL1 is subject to three post-translational modifications including two differing types of phosphorylation seen in viable versus apoptosing cells. The MCL1 phosphorylation seen in viable cells is not associated with a change in electrophoretic mobility; in contrast, the MCL1 phosphorylation seen in cells exposed to certain apoptosis-inducing agents is associated with a distinct change in mobility. MCL1 also undergoes a separate third modification that involves the loss of a segment at the N-terminus. This proposal focuses on these three modifications and on their impact on the anti-apoptotic activity of MCL1 and on the tumorigenesis seen in the MCL1 transgenic mice. BCL2 phosphorylation has been variously reported to enhance or to inhibit its anti-apoptotic function, and the fact that MCL1 phosphorylation differs in viable versus apoptosing cells may lend insight into this issue. Given this background, the investigator plans to determine how specific post-translation modifications (i.e., phosphorylation; n-terminal modifications) affects turnover and the anti-apoptotic activity of MCL1. These studies will be complemented by in vivo assessment of the importance of these modifications, utilizing the transgenic system, which the investigator has developed
Keywords: B cell lymphoma, BCL2 gene /protein, carcinogenesis, genetic regulation, posttranslational modification, programmed cell death cell cycle, cell differentiation, gene expression, phosphoprotein, phosphorylation laboratory mouse, transgenic animal
Project start date: 1992-06-01
Project end date: 2005-03-31
2R01CA057359-09 (2000): $321975
GENES EXPRESSED EARLY IN LEUKEMIC CELL DIFFERENTIATION
Ruth W Craig, Professor
Pharmacology And Toxicologydartmouth College
office Of Sponsored Projects
hanover, Nh 03755
Grant 5R29CA054385-04 from National Cancer Institute, IRG: PTHB
Abstract: In the early stages of cell differentiation, certain genes switch off and others switch on. In the ML-1 human myeloblastic leukemia cell line, we have shown that c-myb switches off early in induction with 12-0-tetradecanoylphorbol-13-acetate (TPA). Our goal now is to identify and characterize genes that switch on early in induction. We are making considerable progress towards this goal By optimizing conditions, we shortened the induction period to 1-4 hours (from 1-3 days). Using differential screening, we isolated two CDNA clones which increase in expression (>8fold) during induction with TPA. Expression increases very early (at 1-3 hours), which is prior to the appearance of early differentiation markers (at -0.5-1 day) and differentiated morphology (at -3 days). Thus, these cDNAs represent "early-induction" genes in that they are expressed during commitment to differentiation and before the appearance of maturing phenotype. Interestingly, initial sequence data from one of these cDNAs reveals no extensive areas of homology with other known genes. We now aim to further explore the role of the early-induction genes in differentiation, proliferation, and leukemia (Aim 1). We will monitor the time course of expression with a variety of inducers (versus non-inducers). We will monitor expression under other conditions of changing proliferation and will look for alterations in leukemic cells at various differentiation stages.´ These studies will highlight genes likely to play an important role in early-induction and/or leukemogenesis. We also aim to molecularly characterize the early-induction genes (Aim 2). We are determining cDNA sequence and will examine the regulation of transcription (nuclear run-on assays). We will assess how gene expression affects differentiation (using antisense RNA techniques and gene transfer). Finally, we aim to identify additional early-induction genes (Aim 3), using more sensitive screening techniques. This will involve enriching probes for sequences increased by more than one inducer and depleting them of sequences present in nondifferentiating cells. These studies will advance us towards our long-term goal of understanding the molecular events that underlie the triggering of differentiation in ML-1
Keywords: gene expression, gene induction /repression, molecular oncology, myelogenous leukemia, myeloid stem cell, neoplastic transformation genetic transcription, nucleic acid sequence antisense nucleic acid, chemical carcinogen, genetic manipulation, human subject, northern blotting, transfection
Project start date: 1991-07-01
Project end date: 1996-05-31
5R29CA054385-04 (1994): $119022
7R29CA054385-03 (1993): $113191
CONTROL OF THE SURVIVAL REGULATOR MCL1 AND TUMORIGENESIS
Ruth W Craig, Professor
Dartmouth College Office Of Sponsored Projects Hanover, Nh 03755
Grant 3R01CA057359-13S1 from National Cancer Institute, IRG: HEM
Abstract: Adapted from investigator s ) MCL1 is an anti-apoptotic member of the BCL-2 family that can be rapidly upregulated and a PEST protein that can be rapidly turned over. MCL1 is normally expressed at specific stages of differentiation and in response to specific stimuli. MCL1 transgenic mice have a high probability of developing massive lymph node hyperplasia with long latency leading to malignant lymphoma with high probability. Preliminary data indicate that MCL1 is subject to three post-translational modifications including two differing types of phosphorylation seen in viable versus apoptosing cells. The MCL1 phosphorylation seen in viable cells is not associated with a change in electrophoretic mobility; in contrast, the MCL1 phosphorylation seen in cells exposed to certain apoptosis-inducing agents is associated with a distinct change in mobility. MCL1 also undergoes a separate third modification that involves the loss of a segment at the N-terminus. This proposal focuses on these three modifications and on their impact on the anti-apoptotic activity of MCL1 and on the tumorigenesis seen in the MCL1 transgenic mice. BCL2 phosphorylation has been variously reported to enhance or to inhibit its anti-apoptotic function, and the fact that MCL1 phosphorylation differs in viable versus apoptosing cells may lend insight into this issue. Given this background, the investigator plans to determine how specific post-translation modifications (i.e., phosphorylation; n-terminal modifications) affects turnover and the anti-apoptotic activity of MCL1. These studies will be complemented by in vivo assessment of the importance of these modifications, utilizing the transgenic system, which the investigator has developed.
Keywords: B cell lymphoma, BCL2 gene /protein, apoptosis, carcinogenesis, genetic regulation, posttranslational modification, cell cycle, cell differentiation, gene expression, phosphoprotein, phosphorylation, genetically modified animal, laboratory mouse
Project start date: 1992-06-01
Project end date: 2006-07-31
3R01CA057359-13S1 (2005): $79950
Related Publications
N-terminal truncation of antiapoptotic MCL1, but not G2/M-induced phosphorylation, is associated with stabilization and abundant expression in tumor cells. J Biol Chem. 2007 Aug 17; 282( 33): 23919-36. Epub 2007 Jun 8. PMID: 17561513 Serine 64 phosphorylation enhances the antiapoptotic function of Mcl-1. J Biol Chem. 2007 Jun 22; 282( 25): 18407-17. Epub 2007 Apr 25. PMID: 17463001 
Constitutive androstane receptor (CAR) ligand, TCPOBOP, attenuates Fas-induced murine liver injury by altering Bcl-2 proteins. Hepatology. 2006 Jul; 44( 1): 252-62. PMID: 16799968 Inducer-and cell type-specific regulation of antiapoptotic MCL1 in myeloid leukemia and multiple myeloma cells exposed to differentiation-inducing or microtubule-disrupting agents. Apoptosis. 2006 Aug; 11( 8): 1275-88. PMID: 16761109 
Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. J Clin Invest. 2005 Feb; 115( 2): 359-68. PMID: 15650769 MCL1 is phosphorylated in the PEST region and stabilized upon ERK activation in viable cells, and at additional sites with cytotoxic okadaic acid or taxol. Oncogene. 2004 Jul 8; 23( 31): 5301-15. PMID: 15241487 Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene. 2004 Jun 17; 23( 28): 4818-27. PMID: 15122313 An MCL1-overexpressing Burkitt lymphoma subline exhibits enhanced survival on exposure to serum deprivation, topoisomerase inhibitors, or staurosporine but remains sensitive to 1-beta-D-arabinofuranosylcytosine. Cancer Res. 2002 Feb 1; 62( 3): 892-900. PMID: 11830549