The DREAM complex through its subunit Lin37 cooperates with Rb to initiate quiescence

Mages, Christina Fs; Wintsche, Axel; Bernhart, Stephan H.; Müller, G

doi:10.7554/elife.26876

“…5C; q value < 0.0001). Using a strategy similar to that used for type B and the PRC2 complex, we took advantage of recently published dominant-negative forms of 2 MuvB core members, LIN37 (41) and LIN52 (42). It has been shown that mutations in 2 small domains in LIN37 (CD1 and CD2) result in the loss of the repressive function of the DREAM complex (LIN37-WT [amino acids 1 through 243] and LIN37-DN) (41), and inhibiting phosphorylation of serine28 on LIN52 results in similar phenotypes (LIN52-WT [1 through 116] and LIN52-DN) (42).…”

Section: Resultsmentioning

confidence: 99%

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Patel

¹

,

Wan

²

,

Al‐Ouran

³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.

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“…Using a strategy similar to that used for type B and the PRC2 complex, we took advantage of recently published dominant-negative forms of two MuvB core members, LIN37 (41) and LIN52 (42). It has been shown that mutations in two small domains in LIN37 (CD1 and CD2) result in the loss of the repressive function of the DREAM complex (LIN37-WT (1-243aa) and LIN37-DN) (41), and inhibiting phosphorylation of Serine28 on LIN52 results in similar phenotypes (LIN52-WT (1-116) and LIN52-DN) (42). We performed qRT-PCR analysis of fourteen genes that were all significantly upregulated in type C, some of which were known DREAM targets (MYBL2, FOXM1, TTK, PBK, MELK, and CDK1) (43).…”

Section: Loss Of the Dream Complex In Type Cmentioning

confidence: 99%

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Patel

¹

,

Wan

²

,

Al‐Ouran

³

et al. 2019

Preprint

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Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors. Significance StatementMeningiomas are the most common primary brain tumors. Although most of these tumors are benign, one-fifth will recur despite apparently complete resection. Several studies have demonstrated that genomic approaches can yield important insights into the biology of these tumors. We performed RNA sequencing and whole-exome sequencing of 160 tumors from 140 patients, which identified three distinct groups of meningioma that correlate with recurrence better than the current WHO grading system. Our analysis also revealed that the most aggressive type was characterized by loss of the repressive DREAM complex. These findings should improve prognostication for patients and lead to viable therapeutic targets.

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“…LIN52 mediates MuvB association with p130 to form DREAM (25,28). LIN9 and LIN37 have poorly characterized biochemical functions, but are required for MuvBregulated gene expression (18,29).…”

mentioning

confidence: 99%

Structural mechanism of Myb–MuvB assembly

Guiley

¹

,

Iness

²

,

Saini

³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The MuvB transcriptional regulatory complex, which controls cell-cycle-dependent gene expression, cooperates with B-Myb to activate genes required for the G2 and M phases of the cell cycle. We have identified the domain in B-Myb that is essential for the assembly of the Myb-MuvB (MMB) complex. We determined a crystal structure that reveals how this B-Myb domain binds MuvB through the adaptor protein LIN52 and the scaffold protein LIN9. The structure and biochemical analysis provide an understanding of how oncogenic B-Myb is recruited to regulate genes required for cell-cycle progression, and the MMB interface presents a potential therapeutic target to inhibit cancer cell proliferation.

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The DREAM complex through its subunit Lin37 cooperates with Rb to initiate quiescence

Cited by 45 publications

References 71 publications

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors

Structural mechanism of Myb–MuvB assembly

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