Regulating the BCL2 Family to Improve Sensitivity to Microtubule Targeting Agents

Whitaker, Robert H.; Placzek, William J.

doi:10.3390/cells8040346

Cited by 45 publications

(46 citation statements)

References 108 publications

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“…Upregulation of the anti-apoptotic BCL2 family members in cancers is a common event with various cancer types employing one or a subset of these proteins to tolerate the genomic and energetic stress that often accompanies tumorigenesis 6 . Overexpression of one of the anti-apoptotic BCL2 family proteins, MCL1, has been identified as a mechanism utilized by cancers to evade a number of standard chemotherapies, including taxanes, vinca alkaloids, platinum containing compounds, and radiation 5,[7][8][9][10][11] . More recently, BH3 mimetics have been developed to suppress anti-apoptotic BCL2 family proteins as a method of treating this key mechanism associated with cancer survival [12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

MCL1 binding to the reverse BH3 motif of P18INK4C couples cell survival to cell proliferation

Whitaker

Placzek

2020

Cell Death Dis

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Commitment to cell cycle entry and cellular duplication is a tightly coordinated and regulated process. Once initiated, a series of multiple checkpoints ensure both accurate genomic replication and chromosomal separation. In the event of unsuccessful cell division, parallel pathways exist that induce the cell to undergo programmed cell death, or apoptosis. At the center of such stress-induced, intrinsic apoptotic regulation lies the BCL2 family of pro-and antiapoptotic regulatory proteins. In a proliferative state the balance of pro-and anti-apoptotic signaling proteins would be expected to favor an excess population of anti-apoptotic members. While the anti-apoptotic BCL2 family member, MCL1, has been identified to oversee mitotic progression, direct communication between the BCL2 family and cell proliferation has not been observed. In this study, we demonstrate a direct protein-protein interaction between MCL1 and the G 1 /S checkpoint protein, P18INK4C. This interaction is mediated by a reverse BH3 (rBH3) motif located in P18INK4C's C-terminal ankyrin repeat. MCL1 is further shown to decrease P18INK4C expression and thereby regulate cell cycle entry in a retinoblastoma (RB1)-dependent manner. Our findings establish a mechanism for translation independent and direct communication between the BCL2 family regulation of apoptosis and CDK4/6-RB regulation of early G 1 /S transition during cellular division/growth.

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Section: Introductionmentioning

confidence: 99%

MCL1 binding to the reverse BH3 motif of P18INK4C couples cell survival to cell proliferation

Whitaker

Placzek

2020

Cell Death Dis

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“…The anti-apoptotic proteins, Bcl-2 and Bcl-xL (encoded by BCL2L1), block AIF1 translocation by directly sequestering members of the pro-apoptotic proteins like Bax. Interestingly, MTIs were shown to promote the release of Bax from Bcl-xL by inducing phosphorylation of Bcl-xL 60 . We reason that the high activity level of the AIF pathway reflects the pro-apoptotic pull in the delicate balance between anti-and pro-apoptotic forces.…”

Section: Resultsmentioning

confidence: 99%

Predicting and affecting response to cancer therapy based on pathway-level biomarkers

et al. 2020

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Identifying robust, patient-specific, and predictive biomarkers presents a major obstacle in precision oncology. To optimize patient-specific therapeutic strategies, here we couple pathway knowledge with large-scale drug sensitivity, RNAi, and CRISPR-Cas9 screening data from 460 cell lines. Pathway activity levels are found to be strong predictive biomarkers for the essentiality of 15 proteins, including the essentiality of MAD2L1 in breast cancer patients with high BRCA-pathway activity. We also find strong predictive biomarkers for the sensitivity to 31 compounds, including BCL2 and microtubule inhibitors (MTIs). Lastly, we show that Bcl-xL inhibition can modulate the activity of a predictive biomarker pathway and resensitize lung cancer cells and tumors to MTI therapy. Overall, our results support the use of pathways in helping to achieve the goal of precision medicine by uncovering dozens of predictive biomarkers.

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“…Consistent with the rBH3-1 and rBH3-2 sequences identified in the phage display, the p73 rBH3 sequence contains three of the four conserved hydrophobic amino acids found in the homologous BH3 motif (H2, H3, and H4 listed in Table 1). These hydrophobic residues in the canonical BH3 motif mediate binding to the p2, p3, and p4 hydrophobic pockets previously described in the MCL1 BH3 groove 5,23 . This includes the placement of a conserved methionine at the hydrophobic position H2 which was observed to be integral in maintaining MCL1 affinity.…”

Section: P73 Contains a Putative Rbh3-motif In The Tdmentioning

confidence: 86%

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

et al. 2020

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MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.

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Regulating the BCL2 Family to Improve Sensitivity to Microtubule Targeting Agents

Cited by 45 publications

References 108 publications

MCL1 binding to the reverse BH3 motif of P18INK4C couples cell survival to cell proliferation

MCL1 binding to the reverse BH3 motif of P18INK4C couples cell survival to cell proliferation

Predicting and affecting response to cancer therapy based on pathway-level biomarkers

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

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