RESUMO
The Participation of myeloid cell leukemia-1 (MCL-1), an antiapoptotic protein, in DNA repair and homologous recombination (HR) is not well understood. This study tests whether MCL-1 interacts with Males absent On First (MOF) to regulate H4K16 acetylation that promotes HR repair in response to replication stress induced by Hydroxyurea (HU) treatment. Co-immunoprecipitation of FLAG-MCL-1 from cancer cells treated with HU pulls down a complex of MCL-1, MOF and BH3-interacting domain death agonist (BID). The same complex is pulled down in cells treated with HU that express FLAG-MOF. MCL-1 regulates H4K16 acetylation during HU-induced replication stress since knockdown of MCL-1 decreases H4K16 acetylation while re-expression of MCL-1 restores H4K16 acetylation. Furthermore, knockdown of BID rescues the clonogenic survival in MCL-1 depleted cells in response to replication stress which is associated with decreased Caspase 3/7 activity compared to MCL-1 depleted cells. Cells depleted in both MCL-1 and BID display increased HR repair efficiency by direct repeats-green fluorescent protein assay and in response to HU exhibit increased ATR, Chk1, and RPA phosphorylation relative to MCL-1 depleted cells. This study uncovers that MCL-1 cooperates with MOF and regulates HR repair through H4K16 acetylation. Further, this study determines that MCL-1 and BID cooperate to regulate the crosstalk between HR repair and apoptosis.
Assuntos
Reparo do DNA , Histona Acetiltransferases , Proteína de Sequência 1 de Leucemia de Células Mieloides , Reparo de DNA por Recombinação , Acetilação , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3 , Histona Acetiltransferases/genética , Histona Acetiltransferases/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Processamento de Proteína Pós-TraducionalRESUMO
Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ "cancer stem cells," such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000-50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-beta-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf(+/-) mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-beta signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf(+/-) mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-beta signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-beta pathway.
Assuntos
Interleucina-6/metabolismo , Neoplasias Hepáticas/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Proliferação de Células , Separação Celular , Regulação para Baixo , Perfilação da Expressão Gênica , Glicoproteínas/deficiência , Glicoproteínas/genética , Glicoproteínas/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Knockout , Proteínas Secretadas Inibidoras de Proteinases , Fator de Transcrição STAT3/metabolismoRESUMO
PURPOSE: To update the recommendations for the use of tumor marker tests in the prevention, screening, treatment, and surveillance of gastrointestinal cancers. METHODS: For the 2006 update, an update committee composed of members from the full Panel was formed to complete the review and analysis of data published since 1999. Computerized literature searches of Medline and the Cochrane Collaboration Library were performed. The Update Committee's literature review focused attention on available systematic reviews and meta-analyses of published tumor marker studies. RECOMMENDATIONS AND CONCLUSION: For colorectal cancer, it is recommended that carcinoembryonic antigen (CEA) be ordered preoperatively, if it would assist in staging and surgical planning. Postoperative CEA levels should be performed every 3 months for stage II and III disease for at least 3 years if the patient is a potential candidate for surgery or chemotherapy of metastatic disease. CEA is the marker of choice for monitoring the response of metastatic disease to systemic therapy. Data are insufficient to recommend the routine use of p53, ras, thymidine synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, microsatellite instability, 18q loss of heterozygosity, or deleted in colon cancer (DCC) protein in the management of patients with colorectal cancer. For pancreatic cancer, CA 19-9 can be measured every 1 to 3 months for patients with locally advanced or metastatic disease receiving active therapy. Elevations in serial CA 19-9 determinations suggest progressive disease but confirmation with other studies should be sought. New markers and new evidence to support the use of the currently reviewed markers will be evaluated in future updates of these guidelines.