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1.
Learn Mem ; 26(9): 332-342, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31416906

RESUMO

Formation of eukaryotic initiation factor 4F (eIF4F) is widely considered to be the rate-limiting step in cap-dependent translation initiation. Components of eIF4F are often up-regulated in various cancers, and much work has been done to elucidate the role of each of the translation initiation factors in cancer cell growth and survival. In fact, many of the basic mechanisms describing how eIF4F is assembled and how it functions to regulate translation initiation were first investigated in cancer cell lines. These same eIF4F translational control pathways also are relevant for neuronal signaling that underlies long-lasting synaptic plasticity and memory, and in neurological diseases where eIF4F and its upstream regulators are dysregulated. Although eIF4F is important in cancer and for brain function, there is not always a clear path to use the results of studies performed in cancer models to inform one of the roles that the same translation factors have in neuronal signaling. Issues arise when extrapolating from cell lines to tissue, and differences are likely to exist in how eIF4F and its upstream regulatory pathways are expressed in the diverse neuronal subtypes found in the brain. This review focuses on summarizing the role of eIF4F and its accessory proteins in cancer, and how this information has been utilized to investigate neuronal signaling, synaptic function, and animal behavior. Certain aspects of eIF4F regulation are consistent across cancer and neuroscience, whereas some results are more complicated to interpret, likely due to differences in the complexity of the brain, its billions of neurons and synapses, and its diverse cell types.


Assuntos
Neoplasias Encefálicas/genética , Encéfalo/metabolismo , Fator de Iniciação 4F em Eucariotos/biossíntese , Regulação Neoplásica da Expressão Gênica , Biossíntese de Proteínas , Animais , Humanos , RNA Mensageiro/genética , Transdução de Sinais
2.
Neuromuscul Disord ; 24(11): 978-81, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25047668

RESUMO

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by a trinucleotide (CAG) repeat expansion in the androgen receptor gene. Patients with SBMA have weakness, atrophy, and fasciculations in the bulbar and extremity muscles. Individuals with CAG repeat lengths greater than 62 have not previously been reported. We evaluated a 29year old SBMA patient with 68 CAGs who had unusually early onset and findings not seen in others with the disease. Analysis of the androgen receptor gene confirmed the repeat length of 68 CAGs in both peripheral blood and fibroblasts. Evaluation of muscle and sensory function showed deficits typical of SBMA, and in addition the patient had manifestations of autonomic dysfunction and abnormal sexual development. These findings extend the known phenotype associated with SBMA and shed new insight into the effects of the mutated androgen receptor.


Assuntos
Transtornos Musculares Atróficos/genética , Receptores Androgênicos/genética , Repetições de Trinucleotídeos/genética , Adulto , Humanos , Imageamento por Ressonância Magnética , Masculino , Debilidade Muscular/etiologia , Transtornos Musculares Atróficos/complicações , Fibras Nervosas/patologia
3.
Neurobiol Dis ; 70: 12-20, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24925468

RESUMO

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is a motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. Although degeneration occurs in the spinal cord and muscle, the exact mechanism is not clear. Induced pluripotent stem cells from spinal and bulbar muscular atrophy patients provide a useful model for understanding the disease mechanism and designing effective therapy. Stem cells were generated from six patients and compared to control lines from three healthy individuals. Motor neurons from four patients were differentiated from stem cells and characterized to understand disease-relevant phenotypes. Stem cells created from patient fibroblasts express less androgen receptor than control cells, but show androgen-dependent stabilization and nuclear translocation. The expanded repeat in several stem cell clones was unstable, with either expansion or contraction. Patient stem cell clones produced a similar number of motor neurons compared to controls, with or without androgen treatment. The stem cell-derived motor neurons had immunoreactivity for HB9, Isl1, ChAT, and SMI-32, and those with the largest repeat expansions were found to have increased acetylated α-tubulin and reduced HDAC6. Reduced HDAC6 was also found in motor neuron cultures from two other patients with shorter repeats. Evaluation of stably transfected mouse cells and SBMA spinal cord showed similar changes in acetylated α-tubulin and HDAC6. Perinuclear lysosomal enrichment, an HDAC6 dependent process, was disrupted in motor neurons from two patients with the longest repeats. SBMA stem cells present new insights into the disease, and the observations of reduced androgen receptor levels, repeat instability, and reduced HDAC6 provide avenues for further investigation of the disease mechanism and development of effective therapy.


Assuntos
Atrofia Bulboespinal Ligada ao X/fisiopatologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurônios Motores/fisiologia , Acetilação , Adulto , Idoso , Atrofia Bulboespinal Ligada ao X/genética , Células Cultivadas , Expansão das Repetições de DNA , Feminino , Fibroblastos/fisiologia , Desacetilase 6 de Histona , Histona Desacetilases/deficiência , Humanos , Masculino , Pessoa de Meia-Idade , Neurogênese/fisiologia , Receptores Androgênicos/metabolismo , Tubulina (Proteína)/metabolismo , Adulto Jovem
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