Enhanced autophagic cell death in expanded polyhistidine variants of HOXA1 reduces PBX1-coupled transcriptional activity and inhibits neuronal differentiation.
HOXA1 is a member of the homeobox gene family and is involved in early brain development. In our previous study, we identified novel variants of polyhistidine repeat tract in HOXA1 gene and showed that ectopic expression of expanded variants led to enhanced intranuclear aggregation and accelerated cell death in a time-dependent manner. Here, we further investigate the implications of polyhistidine variants on HOXA1 function. Aside from intranuclear aggregation, we observed cytosolic aggregates during the early stages of expression. Rapamycin, an autophagy inducer, resulted in decreased protein aggregation and cell death. Here, we also show an interaction between variants of HOXA1 and one of the HOX protein known cofactors, PBX1. Expanded HOXA1 variants exhibited reduced PBX1-coupled transcriptional activity through a regulatory enhancer of HOXB1. Moreover, we demonstrate that both deleted and expanded variants inhibited neurite outgrowth in retinoic acid-induced neuronal differentiation in neuroblastoma cells. These results provide further evidence that expanded polyhistidine repeats in HOXA1 enhance aggregation and cell death, resulting in impaired neuronal differentiation and cooperative binding with PBX1.
Paraguison
Rubigilda C
RC
Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, Yonago, Japan.
Higaki
Katsumi
K
Yamamoto
Kenji
K
Matsumoto
Hideo
H
Sasaki
Tsukasa
T
Kato
Nobumasa
N
Nanba
Eiji
E
D000818:Animals; D001343:Autophagy; D019556:COS Cells; D002449:Cell Aggregation; D016923:Cell Death; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D005822:Genetic Vectors; D006639:Histidine; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000099261:Homeobox A1 Protein
D004268:DNA-Binding Proteins; D006639:Histidine; D018398:Homeodomain Proteins; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C083400:PBX1 protein, human; C033223:polyhistidine