Biology using engineering tools

Birtwistle, Marc R.; Kölch, Walter

doi:10.4161/cc.10.13.16245

Cited by 23 publications

(15 citation statements)

References 73 publications

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“…As expected, we detected reduced levels of pAkt (T308) and Akt (Figure 4A). This strong correlation with PI3K genes (Figure 3E and Figure 4A) would provide a powerful advantage to melanoma progression, since parallel activation of the PI3K may offset the negative feedback induced by ERK [18, 19] in BRAF V600E cells [20]. …”

Section: Discussionmentioning

confidence: 99%

RMEL3, a novel BRAFV600E-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma

et al. 2016

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Previous work identified RMEL3 as a lncRNA with enriched expression in melanoma. Analysis of The Cancer Genome Atlas (TCGA) data confirmed RMEL3 enriched expression in melanoma and demonstrated its association with the presence of BRAFV600E. RMEL3 siRNA-mediated silencing markedly reduced (95%) colony formation in different BRAFV600E melanoma cell lines. Multiple genes of the MAPK and PI3K pathways found to be correlated with RMEL3 in TCGA samples were experimentally confirmed. RMEL3 knockdown led to downregulation of activators or effectors of these pathways, including FGF2, FGF3, DUSP6, ITGB3 and GNG2. RMEL3 knockdown induces gain of protein levels of tumor suppressor PTEN and the G1/S cyclin-Cdk inhibitors p21 and p27, as well as a decrease of pAKT (T308), BRAF, pRB (S807, S811) and cyclin B1. Consistently, knockdown resulted in an accumulation of cells in G1 phase and subG0/G1 in an asynchronously growing population. Thus, TCGA data and functional experiments demonstrate that RMEL3 is required for MAPK and PI3K signaling, and its knockdown decrease BRAFV600E melanoma cell survival and proliferation.

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Section: Discussionmentioning

confidence: 99%

RMEL3, a novel BRAFV600E-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma

et al. 2016

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“…The Raf/MAPK kinase (MEK)/extracellular signal-regulated kinase (ERK) network, which is most closely related to the cell wall integrity pathway, also exhibits negative feedback control and has been proposed to act similarly to a negative feedback amplifier ( Sturm et al. , 2010 ) to limit the duration of responses and produce more graded responses to a broad range of inputs ( Birtwistle and Kolch, 2011 ). When Clp1 was released from the nucleolus in a Pmk1-dependent manner, an increasing number of cells responded to H 2 O 2 for 30 min; however, afterward Clp1 began to transition back to the nucleolus.…”

Section: Discussionmentioning

confidence: 99%

Multiple protein kinases influence the redistribution of fission yeast Clp1/Cdc14 phosphatase upon genotoxic stress

Broadus

Gould

2012

MBoC

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“…For example, the phosphorylation of cdc25C by cdk1, which is a critical step driving the cell cycle transition from G2 into mitosis, was shown to ensue with positive cooperativity and a Hill coefficient greater than one 16 , resulting in a strong and immediate all-or-none transition into mitosis to avoid the potentially lethal consequences of an uncoordinated transition. Conversely, EGF binding to EGFR ensues with negative cooperativity and a Hill coefficient less than one 17 , which would allow the EGFR system to respond more gradually to a wider range of growth factor concentrations 18 .…”

Section: Introductionmentioning

confidence: 99%

Dimerization-based control of cooperativity

Bouhaddou

Birtwistle

2014

Mol. BioSyst.

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Cooperativity of ligand-receptor binding influences the input-output behavior of a biochemical system and thus is an important determinant of its physiological function. Canonically, such cooperativity is understood in terms of ligand-receptor binding affinity, where an initial binding event changes the affinity for subsequent binding events. Here, we demonstrate that dimerization—a simple yet pervasive signaling motif across biology—can have significant control over cooperativity and even dominate over the canonical mechanism. Through an exhaustive parameter sensitivity analysis of a general kinetic model for signal-mediated dimerization, we show that quantitative modulation of dimerization processes can reinforce, eliminate, and even reverse cooperativity imposed by the canonical allosteric ligand-receptor binding affinity mechanism. The favored accumulation of stoichiometrically asymmetric dimers (those with ligand-receptor stoichiometry of 1:2) is a major determinant of dimerization-based cooperativity control. However, simulations demonstrate that favoring accumulation of such stoichiometrically asymmetric dimers can either increase or decrease cooperativity, and thus the quantitative relationship between stoichiometrically asymmetric dimers and cooperativity is highly dependent on the parameter values of the particular system of interest. These results suggest that the dimerization motif provides a novel mechanism for both generating and quantitatively tuning cooperativity that, due to the ubiquity of dimerization motifs in biochemical systems, may play a major role in a host of biological functions. Thus, the canonical, allosteric view of cooperativity is incomplete without considering dimerization effects, which is of particular importance as dimerization is often a necessary feature of the allosteric mechanism.

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Biology using engineering tools

Cited by 23 publications

References 73 publications

RMEL3, a novel BRAFV600E-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma

RMEL3, a novel BRAFV600E-associated long noncoding RNA, is required for MAPK and PI3K signaling in melanoma

Multiple protein kinases influence the redistribution of fission yeast Clp1/Cdc14 phosphatase upon genotoxic stress

Dimerization-based control of cooperativity

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