Neuronal differentiation of PC12 cells induced by engrailed homeodomain is DNA-binding specific and independent of MAP kinases.
Neuronal differentiation may be induced by different mechanisms. In PC12 cells, differentiation can be achieved after stimulation by nerve growth factor through the sustained activation and nuclear translocation of MAPKs. A peptide covering the homeodomain of Drosophila Antennapedia translocates through the cell membrane in primary neurons in culture and reaches their nuclei. This process accelerates neurite elongation. We have examined whether the capacity for neuronal induction is a general characteristic of homeodomains, and whether differentiation proceeds through the same pathway as that induced by growth factors or represents a distinct cellular response. We show here that Engrailed homeodomain is internalized by UR61 cells, a PC12 cell derivative, and that it promotes and sustains neurite outgrowth. This event appears to proceed independently of MAPKs activation, suggesting that either parallel signal transduction pathways are under the control of homeoproteins or that they act downstream of MAPKs. The Fushi tarazu homeodomain also causes neurite outgrowth in UR61 cells and the neurotrophic activities of Engrailed and Fushi tarazu homeodomains correlate with their DNA binding specificities. However, neurite outgrowth is not promoted by Bicoid homeodomain, which recognizes a different DNA sequence. Therefore, the neurotrophic activity of the homeodomains depends not only on DNA-binding ability but also on the specificity of this binding.
Instituto de Investigaciones Biomédicas, CSIC, Departamento de Bioquímica y Biofísica, Facultad de Medicina, Universidad Autónoma de Madrid, Arturo Duperier 4, Spain.
J M
JM
Cosgaya
A
A
Aranda
J
J
Cruces
E
E
Martín-Blanco
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins; D004789:Enzyme Activation; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014157:Transcription Factors
D029721:Drosophila Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C056478:bcd protein, Drosophila; C106185:engrailed homeobox proteins; C497169:ftz protein, Drosophila; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases