Structure-Function Analysis of the Mcl-1 Protein Identifies a Novel Senescence-regulating Domain

Demelash, Abeba; Pfannenstiel, Lukas W.; Tannenbaum, Charles S.; Li, Xiaoxia; Kalady, Matthew F.; DeVecchio, Jennifer; Gastman, Brian

doi:10.1074/jbc.m115.663898

Cited by 15 publications

(22 citation statements)

References 47 publications

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“…In the current study, we demonstrate that targeting Mcl-1 during senescence-inducing doxorubicin treatment in otherwise senescence-resistant cells causes activation of the ROS-dependent DNA damage response (DDR), which is critical for the induction of senescence in cancer [ 11 ]. Consistent with our previous discoveries, we find that Mcl-1′s unique senescence-inhibiting domain is responsible for abrogating ROS production [ 10 ]. We further show that mitochondrial ROS is necessary for the induction of senescence.…”

Section: Introductionsupporting

confidence: 92%

“…Consistent with our previous discoveries, we find that Mcl-1′s unique senescence-inhibiting domain is responsible for abrogating ROS production [10]. We further show that mitochondrial ROS is necessary for the induction of senescence.…”

Section: Introductionsupporting

confidence: 92%

“…However, in our model of CIS, Mcl-1 prevents accumulation of these DNA damage factors, which would preclude direct binding as the only role for Mcl-1 [9, 10]. Figure 1A reveals that under CIS conditions induced by low-dose doxorubicin (DOX+) in CIS resistant, HCT116 p53 −/− (shcontrol) cells, there is little expression of activated DDR components (phospho-ATM, ATR CHK1/2).…”

Section: Resultsmentioning

confidence: 99%

“…We recently showed that Mcl-1 contains an additional unique domain that is distinct among Bcl-2 family members and critical for its known ability to inhibit chemotherapy-induced senescence (but not apoptosis) [ 9 , 10 ]. This observation may explain why current targeted therapies do not completely inhibit Mcl-1 activity, as they do not account for this domain.…”

Section: Introductionmentioning

confidence: 99%

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Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence

et al. 2017

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Mcl-1, a Bcl-2 family member, is highly expressed in a variety of human cancers and is believed to enhance tumorigenic potential and chemotherapy resistance through the inhibition of apoptosis and senescence. We previously reported that Mcl-1′s regulation of chemotherapy-induced senescence (CIS) is dependent on its ability to prevent reactive oxygen species (ROS) generation. In this report, we demonstrate that Mcl-1-regulated CIS requires not only ROS, but specifically mitochondrial ROS, and that these events are upstream of activation of the DNA damage response, another necessary step toward senescence. Mcl-1′s anti-senescence activity also involves the unique ability to inhibit ROS formation by preventing the upregulation of pro-oxidants. Specifically, we found that NADPH oxidases (NOXs) are regulated by Mcl-1 and that NOX4 expression in particular is a required step for CIS induction that is blocked by Mcl-1. Lastly, we illustrate that by preventing expression of NOX4, Mcl-1 limits its availability in the mitochondria, thereby lowering the production of mitochondrial ROS during CIS. Our studies not only define the essential role of Mcl-1 in chemoresistance, but also for the first time link a key pro-survival Bcl-2 family member with the NOX protein family, both of which have significant ramifications in cancer progression.

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Section: Introductionsupporting

confidence: 92%

Section: Introductionsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence

et al. 2017

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“…72 Immunofluorescent staining of cells and tissues sections was performed as described. 73 Quantification of immunofluorescence images was performed using ImageJ software (https:// imagej.nih.gov/ij/).…”

Section: Antibodies Immunofluorescence and Flow Cytometrymentioning

confidence: 99%

Combination PD-1 blockade and irradiation of brain metastasis induces an effective abscopal effect in melanoma

et al. 2018

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2019) Combination PD-1 blockade and irradiation of brain metastasis induces an effective abscopal effect in melanoma, OncoImmunology, 8:1, e1507669, ABSTRACT Nearly half of melanoma patients develop brain metastases during the course of their disease. Despite advances in both localized radiation and systemic immunotherapy, brain metastases remain difficult to treat, with most patients surviving less than 5 months from the time of diagnosis. While both treatment regimens have individually shown considerable promise in treating metastatic melanoma, there is interest in combining these strategies to take advantage of potential synergy. In order to study the ability of local radiation and anti-PD-1 immunotherapy to induce beneficial anti-tumor immune responses against distant, unirradiated tumors, we used two mouse models of metastatic melanoma in the brain, representing BRAF mutant and non-mutant tumors. Combination treatments produced a stronger systemic anti-tumor immune response than either treatment alone. This resulted in reduced tumor growth and larger numbers of activated, cytotoxic CD8 + T cells, even in the unirradiated tumor, indicative of an abscopal effect. The immune-mediated effects were present regardless of BRAF status. These data suggest that irradiation of brain metastases and anti-PD-1 immunotherapy together can induce abscopal anti-tumor responses that control both local and distant disease. ARTICLE HISTORY

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Mcl‐1 targeting could be an intriguing perspective to cure cancer

Blasio

Vento

Fiore

2018

Journal Cellular Physiology

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The Bcl-2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl-1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl-2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl-1 expression is regulated independent of Bcl-2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy is apoptosis. Mcl-1 is a potent oncogene that is regulated at the transcriptional, posttranscriptional, and posttranslational levels. Mcl-1 is a short-lived protein that, in the NH2 terminal region, contains sites for posttranslational regulation that can lead to proteasomal degradation. The USP9X Mcl-1 deubiquitinase regulates Mcl-1 and the levels of these two proteins are strongly correlated. Mcl-1 has three splicing variants (the antiapoptotic protein Mcl-1L and the proapoptotic proteins Mcl-1S and Mcl-1ES), each contributing toward apoptosis regulation. In cancers responsible for the most deaths in the world, the presence of Mcl-1 is associated with malignant cell growth and evasion of apoptosis. Mcl-1 is also one of the key regulators of cancer stem cells' self-renewal that contributes to tumor survival. A great number of indirect and selective Mcl-1 inhibitors have been produced and some of these have shown efficacy in several clinical trials. Thus, therapeutic manipulation of Mcl-1 can be a useful strategy to combat cancer.

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Structure-Function Analysis of the Mcl-1 Protein Identifies a Novel Senescence-regulating Domain

Cited by 15 publications

References 47 publications

Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence

Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence

Combination PD-1 blockade and irradiation of brain metastasis induces an effective abscopal effect in melanoma

Mcl‐1 targeting could be an intriguing perspective to cure cancer

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