دانلود رایگان مقاله تشکیل پروتئین پیچیده و پویایی اینترانوکلیر NAC1 در سلول سرطانی

Abstract

Nucleus accumbens-associated protein 1 (NAC1) is a cancer-related transcription regulator protein that is also involved in the pluripotency and differentiation of embryonic stem cells. NAC1 is overexpressed in various carcinomas including ovarian, cervical, breast, and pancreatic carcinomas. NAC1 knock-down was previously shown to result in the apoptosis of ovarian cancer cell lines and to rescue their sensitivity to chemotherapy, suggesting that NAC1 may be a potential therapeutic target, but protein complex formation and the dynamics of intranuclear NAC1 in cancer cells remain poorly understood. In this study, analysis of HeLa cell lysates by fast protein liquid chromatography (FPLC) on a sizing column showed that the NAC1 peak corresponded to an apparent molecular mass of 300–500 kDa, which is larger than the estimated molecular mass (58 kDa) of the protein. Furthermore, live cell photobleaching analyses with green fluorescent protein (GFP)-fused NAC1 proteins revealed the intranuclear dynamics of NAC1. Collectively our results demonstrate that NAC1 forms a protein complex to function as a transcriptional regulator in cancer cells.

4. Discussion

The present study indicates that NAC1 forms 300e500 kDa protein complexes in HeLa cervical cancer cells. We previously reported that high NAC1 expression in either solid tumors or effusions was significantly correlated with shorter progression-free survival in ovarian cancer patients [12,34]. In pancreatic adenocarcinoma, conversely, a low NAC1 expression level was related to worse oncologic features such as incidence of lymphatic metastasis, venous invasion, and high TNM grading [22]. In neuronal cells, NAC1 is known to interact with the histone deacetylases HDAC3 (49 kDa) and HDAC4 (119 kDa) [35], and with REST corepressor 1 (CoREST, 53 kDa) [36], but not with other corepressors (Nuclear receptor corepressor 1 (NCoR), Nuclear receptor corepressor 2 (NCoR2, also known as SMRT), or mSin3a) [35]. It is conceivable that NAC1 forms a relatively large molecular complex that functions as a repressor complex in neuronal cells. Unfortunately, the molecular mass of this complex has not been elucidated. Given that the ovary, pancreas and neurons originate from the mesoderm, endoderm and ectoderm, respectively, NAC1 may have diverse functions in different cancer cell types, and between cancer and neuronal cells. It is therefore important to specifically identify the additional components of the NAC1-containing complex or complexes in cancer and neuronal cells.