AEC-associated p63 mutations lead to alternative splicing/protein stabilization of p63 and modulation of Notch signaling.
p63, the major regulator of epithelial development/differentiation, is mutated in human ectodermal dysplasias, such as ankyloblepharon, ectodermal dysplasia and clefting (AEC). We recently identified that p63alpha physically associated with mRNA processing/splicing proteins. We previously showed that p63 mutations mapped to the sterile alpha-motif led to disruption of these interactions and modulated an aberrant splicing of keratinocyte growth factor receptor contributing into molecular mechanism underlying AEC phenotype. To further investigate the molecular mechanisms associated with AEC syndrome we established the cellular model for this disorder by stable introduction of mutated allele [L514F] of p63alpha into immortalized keratinocyte cells. We showed that mutated DeltaNp63alpha mediated an aberrant splicing of its own p63 mRNA transcript, which in turn led to accumulation of proteasome-resistant C-terminal truncated p63. The truncated p63 failed to associate with the C-terminal domain of RNA polymerase II through SRA4 protein and, therefore affected keratinocyte proliferation, differentiation and survival and may strongly contribute to AEC phenotype.
Huang
Yi-Ping
YP
Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Kim
Yuriy
Y
Li
Zhaobo
Z
Fomenkov
Tanya
T
Fomenkov
Alexey
A
Ratovitski
Edward A
EA
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002945:Cisplatin / Q000494:pharmacology; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000378:metabolism*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*
C103749:HNRNPAB protein, human; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051880:Receptors, Notch; D015534:Trans-Activators; D012319:RNA Polymerase II; D046988:Proteasome Endopeptidase Complex; D008239:Lysine; D002945:Cisplatin