RESUMO
The tumor suppressor, microRNA-34 (miR-34), a transcriptional target of TP53, functions in a positive feedback loop to activate TP53. Although miR-34 can inhibit cancer cells carrying TP53 mutations, this feedback to TP53 may be a prerequisite for full miR-34 function and may restrict its therapeutic application to patients with intact TP53. To investigate the functional relationships between TP53 and miR-34, and that of other TP53-regulated miRNAs including miR-215/192, we have used a panel of isogenic cancer cell lines that differ only with respect to their endogenous TP53 status. miR-34-induced inhibition of cancer cell growth is the same in TP53-positive and TP53-negative cells. In contrast, miR-215/192 functions through TP53. In the absence of TP53, miR-34, but not miR-215/192, is sufficient to induce an upregulation of the cell cycle-dependent kinase inhibitor p21(CIP1/WAF1). We identify histone deacetylase 1 (HDAC1) as a direct target of miR-34 and demonstrate that repression of HDAC1 leads to an induction of p21(CIP1/WAF1) and mimics the miR-34 cellular phenotype. Depletion of p21(CIP1/WAF1) specifically interferes with the ability of miR-34 to inhibit cancer cell proliferation. The data suggest that miR-34 controls a tumor suppressor pathway previously reserved for TP53 and provides an attractive therapeutic strategy for cancer patients irrespective of TP53 status.
Assuntos
Pontos de Checagem do Ciclo Celular , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/genética , Histona Desacetilase 1/genética , MicroRNAs/genética , MicroRNAs/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Repressão Enzimática , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Neoplasias/terapia , Proteína Supressora de Tumor p53/genéticaRESUMO
The number of couples delaying childbirth is increasing and one out of five American women is having a first child after the age of 35. As a consequence, infertility is becoming more commonplace and the challenges in reproductive health and infertility are growing. The need for innovative research is as compelling as ever. The keys to research in the field over the next several years are furthering our understanding of the biology of reproduction and targeting unmet medical needs.
Assuntos
Infertilidade/terapia , Medicina Reprodutiva , Indústria Farmacêutica , Humanos , PesquisaRESUMO
The objective of this study was to assess the potential of phentolamine as a treatment of postmenopausal women with female arousal disorder (FSAD). Vaginal photoplethismography and a subjective questionnaire were used. Forty one women were enrolled and four treatments were tested: vaginal solutions 5 mg and 40 mg and an oral tablet each of 40 mg of phentolamine and placebo. Physiological readings were significantly different from placebo in the women using hormone replacement therapy (HRT) with 40 mg of phentolamine in vaginal solution (p = 0.0186). Subjective reports also were significantly different from placebo with the vaginal solution 40 mg and the oral tablet of 40 mg of phentolamine among hormone replacement users. No significant differences were found among women not receiving HRT. Results indicate that phentolamine may show promise as treatment for FSAD in estrogenized postmenopausal women.