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Myc - 版本历史
2026-04-19T01:14:45Z
本wiki的该页面的版本历史
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https://www.yiliao.com/index.php?title=Myc&diff=316050&oldid=prev
2026年1月28日 (三) 12:12 77921020
2026-01-28T12:12:50Z
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<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">←上一版本</td>
<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">2026年1月28日 (三) 12:12的版本</td>
</tr><tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l35" >第35行：</td>
<td colspan="2" class="diff-lineno">第35行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">蛋白家族</th></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">蛋白家族</th></div></td></tr>
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<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;"> <tr></ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;"> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">氨基酸数</th></ins></div></td></tr>
<tr><td colspan="2"> </td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div><ins style="font-weight: bold; text-decoration: none;"> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;"><strong>439 aa</strong> (Isoform 2)</td></ins></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <tr></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量</th></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量</th></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">62<del class="diffchange diffchange-inline">-64 </del>kDa</td></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;"><ins class="diffchange diffchange-inline">~49 kDa (表观 ~</ins>62 kDa<ins class="diffchange diffchange-inline">)</ins></td></div></td></tr>
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77921020
https://www.yiliao.com/index.php?title=Myc&diff=316049&oldid=prev
77921020：建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面
2026-01-28T12:10:45Z
<p>建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面</p>
<p><b>新页面</b></p><div><div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff; max-width: 1200px; margin: auto;"><br />
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<strong>Myc</strong>（c-Myc）是由基因 <strong>[[MYC]]</strong> 编码的转录因子，属于 bHLH-LZ 家族。它是人类癌症中最臭名昭著的<strong>原癌蛋白</strong>（Proto-oncogene），在超过 70% 的人类肿瘤中处于过度激活状态。Myc 与其必需伴侣 <strong>[[Max]]</strong> 形成异二聚体，结合 DNA 上的 <strong>E-box</strong> 序列（CACGTG），调控着全基因组约 15% 的基因表达。Myc 的核心功能是作为“通用转录放大器”，驱动核糖体生物合成、细胞周期进程和<strong>[[Warburg效应]]</strong>（糖酵解重编程）。尽管 Myc 被视为癌症治疗的“圣杯”，但由于其缺乏疏水结合口袋的<strong>固有无序</strong>（IDP）特性，长期以来被认为是“不可成药”的靶点，直到近期 <strong>Omomyc</strong> 和 PROTAC 技术的出现才带来转机。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">Myc</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">c-Myc / Master Transcriptional Regulator (点击展开)</div><br />
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[Image:Myc_Max_heterodimer_DNA_structure]<br />
<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">结构：Myc-Max 异二聚体夹住 DNA</div><br />
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<th colspan="2" style="padding: 8px 12px; background-color: #e0f2fe; color: #1e40af; text-align: left; font-size: 0.9em; border-top: 1px solid #bae6fd;">基础参数</th><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">基因符号</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">MYC</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">染色体定位</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">8q24.21 (扩增热点)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">蛋白家族</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">bHLH-LZ</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">62-64 kDa</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">半衰期</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;">极短 (20-30 min)</td><br />
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<th colspan="2" style="padding: 8px 12px; background-color: #e0f2fe; color: #1e40af; text-align: left; font-size: 0.9em; border-top: 1px solid #bae6fd;">功能机制</th><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">必需伴侣</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #16a34a;"><strong>[[Max]]</strong> (无Max不工作)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">DNA基序</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[E-box]] (CACGTG)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">结构特征</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>[[IDP]]</strong> (固有无序蛋白)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">拮抗因子</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #64748b;">Mad, Mxi1 (竞争结合Max)</td><br />
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<th colspan="2" style="padding: 8px 12px; background-color: #e0f2fe; color: #1e40af; text-align: left; font-size: 0.9em; border-top: 1px solid #bae6fd;">药物研发</th><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">成药难度</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>不可成药</strong> (Undruggable)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">直接抑制</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #16a34a;">[[Omomyc]] (OMO-103)</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569; border-bottom: 1px solid #e2e8f0;">间接抑制</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[BET抑制剂]] (JQ1), CDK9i</td><br />
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<th style="text-align: left; padding: 6px 12px; background-color: #f8fafc; color: #475569;">PDB 结构</th><br />
<td style="padding: 6px 12px; color: #0f172a;">1NKP (Myc-Max-DNA)</td><br />
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<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子机制：无序中的秩序</h2><br />
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Myc 是一个功能极其强大的转录因子，但它必须遵循严格的分子规则才能发挥作用：<br />
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[Image:Myc_transcriptional_amplification_mechanism]<br />
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<li style="margin-bottom: 12px;"><strong>必需二聚化 (Obligate Heterodimerization)：</strong> <br />
<br>单体的 Myc 蛋白是不稳定的且没有功能的。它必须通过其 bHLH-LZ 结构域与 <strong>[[Max]]</strong> 蛋白形成异二聚体。Max 是 Myc 的“锚”，帮助其稳定并识别 DNA；而 Myc 含有转录激活域（TAD），负责招募 HATs（如 GCN5）和 P-TEFb，从而启动转录。</li><br />
<li style="margin-bottom: 12px;"><strong>通用放大器 (Universal Amplifier)：</strong> <br />
<br>传统观点认为 Myc 调控特定的一组基因。然而，最新模型表明，Myc 会结合到几乎所有活跃的启动子和增强子区域，<strong>非线性地放大</strong>细胞内已经开启的转录程序。这就解释了为什么 Myc 驱动的肿瘤生长极快——它给所有生长相关的基因都踩了一脚油门。</li><br />
<li style="margin-bottom: 12px;"><strong>固有无序 (Intrinsically Disordered)：</strong> <br />
<br>在未结合 Max 和 DNA 时，Myc 的大部分区域（特别是 N 端 TAD）是无固定结构的。这种“像面条一样”的特性使得传统的小分子药物找不到固定的结合口袋（Pocket），这是 Myc 长期难以成药的根本原因。</li><br />
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<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">肿瘤成瘾：癌基因之王</h2><br />
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<h3 style="margin-top: 0; color: #1e40af; font-size: 1.1em;">Myc 驱动的三大效应</h3><br />
<p style="margin-bottom: 0; text-align: justify; font-size: 0.95em; color: #334155;"><br />
1. <strong>核糖体生物合成：</strong> Myc 直接激活 Pol I 和 Pol III，大量制造 rRNA 和 tRNA，为癌细胞的快速分裂提供物质基础。<br />
<br>2. <strong>代谢重编程 (Warburg Effect)：</strong> Myc 上调糖酵解酶（如 LDHA, HK2）和谷氨酰胺转运体，即使在有氧条件下也强行进行糖酵解。<br />
<br>3. <strong>免疫逃逸：</strong> Myc 上调 <strong>[[CD47]]</strong> ("Don't eat me" 信号) 和 <strong>[[PD-L1]]</strong>，帮助肿瘤躲避免疫监视。<br />
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<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">攻克“不可成药”：最新策略</h2><br />
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<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">策略</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">代表药物</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">机制逻辑</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">显性负性蛋白</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>[[Omomyc]]</strong> (OMO-103)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">一种突变的 Myc 微蛋白，能与 Myc 或 Max 形成无活性的二聚体，物理阻断 Myc 结合 DNA。已进入临床试验。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">表观遗传阻断</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[BET抑制剂]] (JQ1, OTX015)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">Myc 的转录高度依赖 BRD4 (BET家族)。抑制 BRD4 可导致 MYC 基因及其下游靶点迅速“熄火”。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">靶向降解</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">Myc-PROTACs</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">利用 E3 连接酶（如 CRBN）强行泛素化 Myc 蛋白，将其送入蛋白酶体降解。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">G4 稳定剂</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">CX-3543</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">稳定 MYC 启动子区域的 <strong>[[G-四链体]]</strong> (G-quadruplex) 结构，阻碍 RNA 聚合酶的通过，抑制 MYC 转录。</td><br />
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<span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献 [Academic Review]</span><br />
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[1] <strong>Dalla-Favera R, et al. (1982).</strong> <em>Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells.</em> <strong>[[PNAS]]</strong>. <br><br />
<span style="color: #475569;">[点评]：历史性发现，确立了 Myc 在伯基特淋巴瘤 t(8;14) 易位中的核心地位，开启了癌基因研究的黄金时代。</span><br />
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[2] <strong>Dang CV. (1999).</strong> <em>c-Myc target genes involved in cell growth, apoptosis, and metabolism.</em> <strong>[[Molecular and Cellular Biology]]</strong>. <br><br />
<span style="color: #475569;">[点评]：Chi Van Dang 首次揭示了 Myc 直接调控代谢基因（如 LDH-A），建立了癌基因与 Warburg 效应的直接联系。</span><br />
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[3] <strong>Soucek L, et al. (2008).</strong> <em>Modelling Myc inhibition as a cancer therapy.</em> <strong>[[Nature]]</strong>. <br><br />
<span style="color: #475569;">[点评]：利用 Omomyc 证明了全身性抑制 Myc 可以清除肿瘤且副作用可控（仅引起可逆的皮肤/肠道改变），打破了“抑制 Myc 会致死”的教条。</span><br />
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Myc · 知识图谱<br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">上游通路</td><br />
<td style="padding: 10px 15px; color: #334155;">[[Wnt]] • [[Notch]] • [[BET]] (BRD4) • [[MAPK]]</td><br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">互作网络</td><br />
<td style="padding: 10px 15px; color: #334155;">[[Max]] (必需) • [[Mad]] (拮抗) • [[Miz-1]] (抑制)</td><br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">下游效应</td><br />
<td style="padding: 10px 15px; color: #334155;">[[核糖体合成]] • [[糖酵解]] • [[CD47]] • [[eIF4E]]</td><br />
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<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle;">药物开发</td><br />
<td style="padding: 10px 15px; color: #334155;">[[Omomyc]] • [[PROTAC]] • [[G4稳定剂]]</td><br />
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