BMP-2 decreases Mash1 stability by increasing Id1 expression.
In neural development, bone morphogenetic proteins (BMPs) restrict neuronal differentiation, thereby promoting the maintenance of progenitor cells or even inducing astrocytogenesis. We report that exposure of neuroendocrine lung carcinoma cells to BMP-2 leads to a rapid decline in steady-state levels of Mash1 protein and some neuron-specific markers. BMP-2 induces a post-transcriptional decrease in Mash1 levels through enhanced degradation. We demonstrate that Mash1 protein stability is tightly regulated by the E47/Id1 expression ratio. Transient induction of Id1 by BMP-2 negatively correlates with Mash1 levels. Furthermore, an ectopic increase in Id1 levels is sufficient to induce degradation of either ectopic or endogenous Mash1, whereas expression of Mash1 in Id1-deficient cells or overexpression of E47 makes Mash1 levels refractory to the addition of BMP-2. Furthermore, we show that the E47/Id1 expression ratio also regulates CK2-mediated phosphorylation of Mash1 on Ser152, which increases interaction of Mash1-E47 heterodimers. We propose a novel mechanism in which the balance between Id and E protein levels regulates not only the transcriptional function but also protein stability of the neurogenic bHLH transcription factor Mash1.
Departament de Ciències Fisiològiques II, Campus de Bellvitge, Universitat de Barcelona, Feixa Llarga s/n, L'Hospitalet de Llobregat, Spain.
Francesc
F
Viñals
Julia
J
Reiriz
Santiago
S
Ambrosio
Ramon
R
Bartrons
Jose Luis
JL
Rosa
Francesc
F
Ventura
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology*; D047390:Casein Kinase II; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D051798:Inhibitor of Differentiation Protein 1; D051379:Mice; D008954:Models, Biological; D009490:Neurosecretory Systems / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta
D051792:Basic Helix-Loop-Helix Proteins; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D047390:Casein Kinase II; D004268:DNA-Binding Proteins; D051798:Inhibitor of Differentiation Protein 1; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D012097:Repressor Proteins; D012694:Serine; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; C544912:TCF7L1 protein, human; C544913:Tcf7l1 protein, mouse; C499469:recombinant human bone morphogenetic protein-2