EGFR signaling defines Mcl<sup>-</sup>1 survival dependency in neuroblastoma

Nalluri, Srilatha; Peirce, Susan K.; Tanos, Rachel; Abdella, Haneen; Karmali, Dipan; Hogarty, Michael D.; Goldsmith, Kelly

doi:10.1080/15384047.2014.1002333

Cited by 22 publications

(19 citation statements)

References 31 publications

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“…Indeed, we speculate that Mcl-1 functions as a molecular clock in this cell type to ensure a controlled population of unstimulated monocytes (49). This idea is consistent with what is known about the antiapoptotic role of Mcl-1 in hematopoietic cells (77) and the way in which dysregulation of Mcl-1 contributes to the development of myeloid (78)(79)(80) and other cancers (81)(82)(83)(84)(85)(86). Mcl-1 was first identified as a result of its overexpression during TPA (12-O-tetradecanoyl phorbol 13-acetate)-induced differentiation of a human myeloid leukemia cell line (ML-1) (87).…”

Section: Discussionsupporting

confidence: 69%

“…Subsequent studies of Mcl-1 have classified the protein as a member of the Bcl-2 family of mitochondrial membrane permeability regulators and defined a dual role for Mcl-1 in myeloid cells: regulating both cell survival and differentiation (77,88). It is the prosurvival function of Mcl-1 that appears to drive the development of myeloid leukemias and other cancers (79,(81)(82)(83)(84)(85)89) in addition to contributing to their drug resistance (89)(90)(91). We have shown that HCMV upregulates Mcl-1 in a transient manner, effectively usurping its prosurvival function to promote early survival of HCMV-infected monocytes (49).…”

Section: Discussionmentioning

confidence: 99%

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Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Collins-McMillen

Kim

Nogalski

et al. 2016

J Virol

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Monocytes IMPORTANCEHematogenous dissemination of HCMV via infected monocytes is a crucial component of the viral survival strategy and is required for the establishment of persistent infection and for viral spread to additional hosts. Our system of infected primary human blood monocytes provides us with an opportunity to answer specific questions about viral spread and persistence in in vivo-relevant myeloid cells that cannot be addressed with the more traditionally used replication-permissive cells. Our goal in examining the mechanisms whereby HCMV reprograms infected monocytes to promote viral dissemination is to uncover new targets for therapeutic intervention that would disrupt key viral survival and persistence strategies. Because of this important role in maintaining survival of HCMV-infected monocytes, our new data on the role of Bcl-2 regulation during viral infection represents a promising molecular target for mitigating viral spread and persistence. H uman cytomegalovirus (HCMV) is a ubiquitous host-restricted betaherpesvirus that infects 60 to 90% of the population and persists for the lifetime of the infected individual (1). HCMV infection results in a wide range of pathogenic outcomes dependent upon the age and immune status of the host (2). Infection of immunocompetent hosts is usually asymptomatic or only mildly symptomatic (3, 4); however, it can cause infectious mononucleosis, is a risk factor for the development of cardiovascular disease (5-9), and has been linked to certain types of cancers in otherwise healthy individuals (10-15). In contrast, HCMV infection leads to significant morbidity and mortality in the immunocompromised. HCMV is an important opportunistic pathogen in AIDS patients (16)(17)(18)(19)(20), is a leading infectious cause of complications in transplant recipients (21-28), and causes severe neurological disease in congenitally infected neonates (29)(30)(31)(32)(33)(34).HCMV pathogenesis and disease result from viral spread to multiple organ sites following primary HCMV infection, a process which appears to be a critical step in the viral persistence strategy, as it allows for the establishment of lifelong persistence within the host, as well as for viral shedding and spread to additional hosts (1,35,36). Monocytes are the primary blood-borne targets for HCMV infection and are thought to be centrally involved in the hematogenous dissemination of the virus to target organ systems (37-41). We propose that HCMV reprograms the biology of infected monocytes, creating the ideal cell type to serve as "Trojan horses" to carry HCMV to target host organ sites and then to

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Collins-McMillen

Kim

Nogalski

et al. 2016

J Virol

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“…A cell with a sufficient reservoir of Mcl-1 protein would therefore be able to readily tolerate this increased proapoptotic load, resulting in both stabilized Mcl-1 and a cancer cell 'primed' with Bim bound to Mcl-1. This could potentially explain the multitude of cell types with demonstrated dependence on Mcl-1 for survival [52][53][54]. Furthermore, while we previously showed that increasing the expression levels of antiapoptotic proteins does not alter the pattern of Bim priming [52], our data suggest that this pattern can in fact be altered by increasing proapoptotic BH3only expression.…”

Section: Discussionmentioning

confidence: 52%

Phosphorylation alters Bim‐mediated Mcl‐1 stabilization and priming

Conage‐Pough

Boise

2018

The FEBS Journal

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Mcl-1 is a highly labile protein, subject to extensive post-translational regulation. This distinguishes Mcl-1 from other antiapoptotic proteins and necessitates further study to better understand how interactions with proapoptotic Bcl-2 proteins affect its regulation. One such protein, Bim, is known to stabilize Mcl-1, and Bim phosphorylation has been associated with increased Mcl-1 binding. Consequently, we investigated the potential impact of Bim phosphorylation on Mcl-1 stability. We found that Bim stabilizes and primes Mcl-1 in RPCI-WM1 cells and is constitutively phosphorylated. Additionally, introduction of several phospho-mimetic and unphosphosphorylateable Bim mutations resulted in altered Mcl-1 stability and distinct Bim binding to antiapoptotic proteins. These findings suggest Bim phosphorylation not only regulates Mcl-1 stability but also is a potential mechanism for enforcing Mcl-1 dependence.

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“…EGFR mutant NSCLC cells upregulate Mcl-1 through mTORC1-mediated mRNA translation, which contributes to EGFR TKI resistance 11 . Moreover, inhibition of EGFR by shRNA or erlotinib disrupts Bim binding to Mcl-1 and restoring the sensitivity to ABT-737 12 . In addition, TKI increase Mcl-1 degradation and, in combination with Bcl-XL/Bcl-2 inhibitors, drive prostate cancer apoptosis 13 .…”

Section: Introductionmentioning

confidence: 99%

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

Gao

et al. 2020

Cell Death Dis

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Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human nonsmall cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/ T790M-mutated EGFR. The in silico docking study indicated that deguelin was docked into the ATP-binding pocket of EGFRs. By suppression of EGFR signaling, deguelin inhibited anchorage-dependent, and independent growth of NSCLC cell lines, and significantly delayed tumorigenesis in vivo. Further study showed that deguelin inhibited EGFR and downstream kinase Akt, which resulted in the activation of GSK3β and eventually enhanced Mcl-1 phosphorylation at S159. Moreover, deguelin promoted the interaction between Mcl-1 and E3 ligase SCF FBW7 , which enhanced FBW7-mediated Mcl-1 ubiquitination and degradation. Additionally, phosphorylation of Mcl-1 by GSK3β is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3β compromised deguelin-induced Mcl-1 ubiquitination and reduction. Taken together, our data indicate that enhancement of ubiquitination-dependent Mcl-1 turnover might be a promising approach for cancer treatment.

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EGFR signaling defines Mcl^-1 survival dependency in neuroblastoma

Cited by 22 publications

References 31 publications

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Phosphorylation alters Bim‐mediated Mcl‐1 stabilization and priming

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

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EGFR signaling defines Mcl-1 survival dependency in neuroblastoma

Cited by 22 publications

References 31 publications

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Human Cytomegalovirus Promotes Survival of Infected Monocytes via a Distinct Temporal Regulation of Cellular Bcl-2 Family Proteins

Phosphorylation alters Bim‐mediated Mcl‐1 stabilization and priming

Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization

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EGFR signaling defines Mcl^-1 survival dependency in neuroblastoma