RESUMO
Vasoinhibins are a family of peptides that act on endothelial cells to suppress angiogenesis and promote apoptosis-mediated vascular regression. Vasoinhibins include the N-terminal fragments from prolactin (PRL), GH, and placental lactogen. One of the vasoinhibins, the N-terminal PRL fragment of 16âkDa, is generated by the lysosomal representative protease cathepsin D (Cath D). Because the normal growth and involution of the mammary gland (MG) are profoundly affected by the expansion and regression of blood vessels and also because PRL stimulates the growth and differentiation of MG, we proposed that intact PRL produced during lactation contributes to MG angiogenesis and increased blood flow, whereas during involution, the N-terminal PRL fragment would have proapoptotic effects on mammary epithelial cells (MECs). Therefore, we investigated the production of the N-terminal PRL fragment and its direct effect on the MG. Mouse PRL (mPRL) was proteolytically cleaved by Cath D between amino acids 148 and 149. N-terminal PRL fragment and Cath D expression increased during MG involution. Furthermore, incubation of MG fragments and MCF7 with recombinant 16âkDa mPRL revealed a proapoptotic effect in MECs. Ectopic mPRL in MECs was cleaved to 16âkDa PRL by Cath D in the MG lysosomal fraction. The majority of PRL derived from pituitary gland was cleaved to 16âkDa PRL in culture medium. Therefore, N-terminal PRL fragment increases during the involution period, has a proapoptotic effect on MECs, and is mainly generated by secreted Cath D in the extracellular space of MG.
Assuntos
Catepsina D/metabolismo , Proteínas de Ciclo Celular/biossíntese , Glândulas Mamárias Animais/fisiologia , Prolactina/metabolismo , Sequência de Aminoácidos , Animais , Apoptose , Catepsina D/biossíntese , Catepsina D/genética , Diferenciação Celular , Linhagem Celular Tumoral , Feminino , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Células MCF-7 , Glândulas Mamárias Animais/irrigação sanguínea , Glândulas Mamárias Animais/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos ICR , Dados de Sequência Molecular , Neovascularização Fisiológica , Prolactina/biossíntese , Prolactina/genética , RNA Mensageiro/biossíntese , Receptores da Prolactina/biossíntese , Receptores da Prolactina/genética , Análise de Sequência de ProteínaRESUMO
We report a 76-year-old man who suddenly had pain in the right buttock that radiated down the back of the leg. He underwent nerve block therapy, but subsequently noted weakness of the right leg. On examination, there was moderate weakness of the right gastrocnemius, flexor digitorum longus and extensor hallcis longus, and mild weakness of the tibialis anterior, quadriceps and hamstrings muscles. The right Achilles tendon reflex was absent. There was a slight diminution of touch sensation over the right L5-S1 area. A nerve conduction study revealed reduced motor and sensory action potentials in the right leg. An electromyography showed evidence of denervation in the right gastrocnemius and tibialis anterior muscles. Treatment with corticosteroids was effective for alleviating his pain, and muscle strength improved gradually. One year later, he showed no neurological deficits. Neuralgic amyotrophy in the lower extremities is rare, but awareness of this disorder helps us avoid unnecessary surgical investigations and leads to possible treatment with immunomodulative therapy.