Calcium-dependent binding of Myc to calmodulin

Raffeiner, Philipp; Schraffl, Andrea; Schwarz, Thomas C.; Röck, Ruth; Ledolter, Karin; Hartl, Markus; Konrat, Robert; Stefan, Eduard; Bister, Klaus

doi:10.18632/oncotarget.13759

Cited by 16 publications

(41 citation statements)

References 44 publications

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“…Immunoblots were performed using anti‐Myc or anti‐Max, respectively. No direct interactions between BASP1 and v‐Myc or between BASP1 and Max were detectable in agreement with previous observations (Hartl et al , ; Raffeiner et al , ).…”

Section: Resultssupporting

confidence: 93%

“…A). Whereas pRc‐BASP1 efficiently suppressed v‐Myc‐mediated transcriptional activation of the WS5 target gene promoter, pRc‐CALM1 led to an increase in transcriptional activation as reported previously (Hartl et al , ; Raffeiner et al , ). In the presence of the BASP1 ED peptide, the transcriptional activation potential was reduced to about 50% (Fig.…”

Section: Resultssupporting

confidence: 83%

“…We have previously shown that v‐Myc does not physically interact with BASP1 (Hartl et al , ) but with the BASP1‐binding partner CaM in a calcium‐dependent manner (Raffeiner et al , ). On the other hand, BASP1 specifically inhibits v‐Myc‐induced cell transformation and transcriptional activation (Hartl et al , ).…”

Section: Resultsmentioning

confidence: 99%

“…To demonstrate that low levels of ectopic CaM suffice to induce a specific biological effect, FLAG‐tagged CaM was co‐expressed with v‐Myc in QEF (Fig. ) and tested for synergistic cell transformation as reported previously (Raffeiner et al , ). The result shows that despite low overexpression, v‐Myc‐induced cell transformation was specifically enhanced in contrast to co‐expression with a FLAG‐tagged keratin control protein (KRN1) (Hartl et al , ) with a size comparable to CaM (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Based on these discoveries, we proposed that BASP1 displays properties of a putative tumor suppressor (Hartl et al , ). BASP1 does not physically interact with v‐Myc (Hartl et al , ), but all MYC variant proteins interact with the BASP1‐interaction partner CaM, possibly pointing to a functional connection between these three proteins (Raffeiner et al , ). Increased CaM levels indeed enhance the transcriptional and oncogenic activities of v‐Myc (Raffeiner et al , ), suggesting that the inhibitory effect of excess BASP1 may be based on interference with the v‐Myc : CaM interaction.…”

Section: Introductionmentioning

confidence: 99%

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The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

et al. 2020

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The MYC protein is a transcription factor with oncogenic potential controlling fundamental cellular processes such as cell proliferation, metabolism, differentiation, and apoptosis. The MYC gene is a major cancer driver, and elevated MYC protein levels are a hallmark of most human cancers. We have previously shown that the brain acid‐soluble protein 1 gene (BASP1) is specifically downregulated by the v‐myc oncogene and that ectopic BASP1 expression inhibits v‐myc‐induced cell transformation. The 11‐amino acid effector domain of the BASP1 protein interacts with the calcium sensor calmodulin (CaM) and is mainly responsible for this inhibitory function. We also reported recently that CaM interacts with all MYC variant proteins and that ectopic CaM increases the transactivation and transformation potential of the v‐Myc protein. Here, we show that the presence of excess BASP1 or of a synthetic BASP1 effector domain peptide leads to displacement of v‐Myc from CaM. The protein stability of v‐Myc is decreased in cells co‐expressing v‐Myc and BASP1, which may account for the inhibition of v‐Myc. Furthermore, suppression of v‐Myc‐triggered transcriptional activation and cell transformation is compensated by ectopic CaM, suggesting that BASP1‐mediated withdrawal of CaM from v‐Myc is a crucial event in the inhibition. In view of the tumor‐suppressive role of BASP1 which was recently also reported for human cancer, small compounds or peptides based on the BASP1 effector domain could be used in drug development strategies aimed at tumors with high MYC expression.

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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

et al. 2020

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Energetic and structural insights behind calcium induced conformational transition in calmodulin

Halder,

Warshel

2023

Proteins

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Calmodulin (CaM) is a key signaling protein that triggers several cellular and physiological processes inside the cell. Upon binding with calcium ion, CaM undergoes large scale conformational transition from a closed state to an open state that facilitates its interaction with various target protein and regulates their activity. This work explores the origin of the energetic and structural variation of the wild type and mutated CaM and explores the molecular origin for the structural differences between them. We first calculated the sequential calcium binding energy to CaM using the PDLD/S‐LRA/β approach. This study shows a very good correlation with experimental calcium binding energies. Next we calculated the calcium binding energies to the wild type CaM and several mutated CaM systems which were reported experimentally. On the structural aspect, it has been reported experimentally that certain mutation (Q41L‐K75I) in calcium bound CaM leads to complete conformational transition from an open to a closed state. By using equilibrium molecular dynamics simulation, free energy calculation and contact frequency map analysis, we have shown that the formation of a cluster of long‐range hydrophobic contacts, initiated by the Q41L‐K75I CaM variant is the driving force behind its closing motion. This study unravels the energetics and structural aspects behind calcium ion induced conformational changes in wild type CaM and its variant.

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MYC and RAF: Key Effectors in Cellular Signaling and Major Drivers in Human Cancer

Stefan

Bister

2017

Current Topics in Microbiology and Immunology

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The prototypes of the human MYC and RAF gene families are orthologs of animal proto-oncogenes that were originally identified as transduced alleles in the genomes of highly oncogenic retroviruses. MYC and RAF genes are now established as key regulatory elements in normal cellular physiology, but also as major cancer driver genes. Although the predominantly nuclear MYC proteins and the cytoplasmic RAF proteins have different biochemical functions, they are functionally linked in pivotal signaling cascades and circuits. The MYC protein is a transcription factor and together with its dimerization partner MAX holds a central position in a regulatory network of bHLH-LZ proteins. MYC regulates transcription conducted by all RNA polymerases and controls virtually the entire transcriptome. Fundamental cellular processes including distinct catabolic and anabolic branches of metabolism, cell cycle regulation, cell growth and proliferation, differentiation, stem cell regulation, and apoptosis are under MYC control. Deregulation of MYC expression by rearrangement or amplification of the MYC locus or by defects in kinase-mediated upstream signaling, accompanied by loss of apoptotic checkpoints, leads to tumorigenesis and is a hallmark of most human cancers. The critically controlled serine/threonine RAF kinases are central nodes of the cytoplasmic MAPK signaling cascade transducing converted extracellular signals to the nucleus for reshaping transcription factor controlled gene expression profiles. Specific mutations of RAF kinases, such as the prevalent BRAF(V600E) mutation in melanoma, or defects in upstream signaling or feedback loops cause decoupled kinase activities which lead to tumorigenesis. Different strategies for pharmacological interference with MYC- or RAF-induced tumorigenesis are being developed and several RAF kinase inhibitors are already in clinical use.

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Calcium-dependent binding of Myc to calmodulin

Cited by 16 publications

References 44 publications

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

The brain acid‐soluble protein 1 (BASP1) interferes with the oncogenic capacity of MYC and its binding to calmodulin

Energetic and structural insights behind calcium induced conformational transition in calmodulin

MYC and RAF: Key Effectors in Cellular Signaling and Major Drivers in Human Cancer

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