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Mastermind-Like 1 Is Ubiquitinated: Functional Consequences for Notch Signaling.

Farshbaf M, Lindberg MJ, Truong A, Bevens Z, Chambers E, Pournara A, Wallberg AE, White JB - PLoS ONE (2015)

Bottom Line: We also show that p300 stimulates ubiquitination and that Notch inhibits ubiquitination.Therefore, we speculate that ubiquitination of MAML1 might be a mechanism to maintain low levels of the protein until needed for transcriptional activation.Our data supports the notion that a precise and tight regulation of the Notch pathway is required for this signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Biological Sciences, San José State University, San José, California, United States of America.

ABSTRACT
Early studies demonstrated the involvement of ubiquitination of the Notch intracellular domain for rapid turnover of the transcriptional complex at Notch target genes. It was shown that this ubiquitination was promoted by the co-activator Mastermind like 1 (MAML1). MAML1 also contains numerous lysine residues that may also be ubiquitinated and necessary for protein regulation. In this study, we show that over-expressed MAML1 is ubiquitinated and identify eight conserved lysine residues which are required for ubiquitination. We also show that p300 stimulates ubiquitination and that Notch inhibits ubiquitination. Furthermore, we show that a mutant MAML1 that has decreased ubiquitination shows increased output from a HES1 reporter gene assay. Therefore, we speculate that ubiquitination of MAML1 might be a mechanism to maintain low levels of the protein until needed for transcriptional activation. In summary, this study identifies that MAML1 is ubiquitinated in the absence of Notch signaling to maintain low levels of MAML1 in the cell. Our data supports the notion that a precise and tight regulation of the Notch pathway is required for this signaling pathway.

No MeSH data available.


Related in: MedlinePlus

Proposed Model for Importance of MAML1 Ubiquitination.In the absence of activators (MEF2C, p53, NICD), MAML1 levels must remain low in the cell in order to prevent nonspecific transcriptional activation. MAML1 interacts with p300 to recruit an ubiquitin ligase to ubiquitinate MAML1 resulting in degradation. When activators are present, MAML1 is stabilized allowing co-transcriptional activation of target genes to occur.
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pone.0134013.g008: Proposed Model for Importance of MAML1 Ubiquitination.In the absence of activators (MEF2C, p53, NICD), MAML1 levels must remain low in the cell in order to prevent nonspecific transcriptional activation. MAML1 interacts with p300 to recruit an ubiquitin ligase to ubiquitinate MAML1 resulting in degradation. When activators are present, MAML1 is stabilized allowing co-transcriptional activation of target genes to occur.

Mentions: We propose a mechanism to account for the ubiquitination and degradation of MAML (Fig 8). In the absence of a transcriptional activator (NICD, p53, MEF2C), MAML1 levels need to remain low in the cell in order to prevent non-specific activation of genes. Increased levels of MAML1 in the nucleus in the absence of one its activators could lead to increased non-specific interaction with other transcription factors and subsequent recruitment of p300 to acetylate histones at target genes. Only when a transcriptional activator is present would MAML1 levels become stabilized allowing proper transcriptional complex formations in the nucleus.


Mastermind-Like 1 Is Ubiquitinated: Functional Consequences for Notch Signaling.

Farshbaf M, Lindberg MJ, Truong A, Bevens Z, Chambers E, Pournara A, Wallberg AE, White JB - PLoS ONE (2015)

Proposed Model for Importance of MAML1 Ubiquitination.In the absence of activators (MEF2C, p53, NICD), MAML1 levels must remain low in the cell in order to prevent nonspecific transcriptional activation. MAML1 interacts with p300 to recruit an ubiquitin ligase to ubiquitinate MAML1 resulting in degradation. When activators are present, MAML1 is stabilized allowing co-transcriptional activation of target genes to occur.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520489&req=5

pone.0134013.g008: Proposed Model for Importance of MAML1 Ubiquitination.In the absence of activators (MEF2C, p53, NICD), MAML1 levels must remain low in the cell in order to prevent nonspecific transcriptional activation. MAML1 interacts with p300 to recruit an ubiquitin ligase to ubiquitinate MAML1 resulting in degradation. When activators are present, MAML1 is stabilized allowing co-transcriptional activation of target genes to occur.
Mentions: We propose a mechanism to account for the ubiquitination and degradation of MAML (Fig 8). In the absence of a transcriptional activator (NICD, p53, MEF2C), MAML1 levels need to remain low in the cell in order to prevent non-specific activation of genes. Increased levels of MAML1 in the nucleus in the absence of one its activators could lead to increased non-specific interaction with other transcription factors and subsequent recruitment of p300 to acetylate histones at target genes. Only when a transcriptional activator is present would MAML1 levels become stabilized allowing proper transcriptional complex formations in the nucleus.

Bottom Line: We also show that p300 stimulates ubiquitination and that Notch inhibits ubiquitination.Therefore, we speculate that ubiquitination of MAML1 might be a mechanism to maintain low levels of the protein until needed for transcriptional activation.Our data supports the notion that a precise and tight regulation of the Notch pathway is required for this signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Biological Sciences, San José State University, San José, California, United States of America.

ABSTRACT
Early studies demonstrated the involvement of ubiquitination of the Notch intracellular domain for rapid turnover of the transcriptional complex at Notch target genes. It was shown that this ubiquitination was promoted by the co-activator Mastermind like 1 (MAML1). MAML1 also contains numerous lysine residues that may also be ubiquitinated and necessary for protein regulation. In this study, we show that over-expressed MAML1 is ubiquitinated and identify eight conserved lysine residues which are required for ubiquitination. We also show that p300 stimulates ubiquitination and that Notch inhibits ubiquitination. Furthermore, we show that a mutant MAML1 that has decreased ubiquitination shows increased output from a HES1 reporter gene assay. Therefore, we speculate that ubiquitination of MAML1 might be a mechanism to maintain low levels of the protein until needed for transcriptional activation. In summary, this study identifies that MAML1 is ubiquitinated in the absence of Notch signaling to maintain low levels of MAML1 in the cell. Our data supports the notion that a precise and tight regulation of the Notch pathway is required for this signaling pathway.

No MeSH data available.


Related in: MedlinePlus