Deep proteome profiling of human mammary epithelia at lineage and age resolution.
Deep proteome profiling of human mammary epithelia at lineage and age resolution.
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DOI：
10.1016/j.isci.2021.103026
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发表时间：
2021-09-24
期刊：
影响因子：
5.8
通讯作者：
LaBarge MA
中科院分区：
文献类型：
--
作者：
Hinz S;Manousopoulou A;Miyano M;Sayaman RW;Aguilera KY;Todhunter ME;Lopez JC;Sohn LL;Wang LD;LaBarge MA
年龄是大多数癌症的主要危险因素，但对人类上皮细胞中蛋白质组如何随年龄变化知之甚少。我们提出了全面的蛋白质组，包括>9,000总蛋白质和>15,000磷酸肽从正常的初级人类乳腺上皮细胞的谱系分辨率从10名妇女的年龄从19岁到68岁。对数据进行质量控制，并使用基于细胞的测定对结果进行生物学验证。使用差异表达分析和加权蛋白质共表达网络分析鉴定了年龄依赖性蛋白质特征。管腔细胞中的基础标志物（包括KRT 14和AXL）的上调是衰老的显著后果。PEAK 1被鉴定为管腔细胞中的年龄依赖性信号激酶，这揭示了靶向消融的潜在年龄依赖性脆弱性。转录组和蛋白质组之间的相关性分析揭示了与年龄相关的蛋白质稳态调节的丧失。乳腺上皮细胞中的依赖性蛋白质组变化确定了迄今未知的降低乳腺癌易感性的潜在治疗靶点。HMEC在谱系分辨率下的蛋白质组学分析蛋白质稳态的丧失是腔上皮谱系特有的在腔细胞中鉴定随年龄变化的共调节蛋白质，包括PEAK 1 PEAK 1抑制选择性地消融较老的腔细胞-起源的癌细胞发育生物学;复杂系统生物学;蛋白质组学
Age is the major risk factor in most carcinomas, yet little is known about how proteomes change with age in any human epithelium. We present comprehensive proteomes comprised of >9,000 total proteins and >15,000 phosphopeptides from normal primary human mammary epithelia at lineage resolution from ten women ranging in age from 19 to 68 years. Data were quality controlled and results were biologically validated with cell-based assays. Age-dependent protein signatures were identified using differential expression analyses and weighted protein co-expression network analyses. Upregulation of basal markers in luminal cells, including KRT14 and AXL, were a prominent consequence of aging. PEAK1 was identified as an age-dependent signaling kinase in luminal cells, which revealed a potential age-dependent vulnerability for targeted ablation. Correlation analyses between transcriptome and proteome revealed age-associated loss of proteostasis regulation. Age-dependent proteome changes in the breast epithelium identified heretofore unknown potential therapeutic targets for reducing breast cancer susceptibility. Age-dependent proteomic profiling of HMECs at lineage resolution Loss of proteostasis is unique to the luminal epithelial lineage with age Identification of co-regulated proteins with age in luminal cells including PEAK1 PEAK1 inhibition selectively ablates older luminal cells – cancer cell of origin Developmental biology; Complex system biology; Proteomics
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
2.7
作者：
Benjamini, Yoav;Krieger, Abba M.;Yekutieli, Daniel
通讯作者：
Yekutieli, Daniel
影响因子：
7.3
作者：
Gao, Mingshan;Duan, Lei;Ding, Ke
通讯作者：
Ding, Ke
影响因子：
82.9
作者：
Kaushik, Susmita;Cuervo, Ana Maria
通讯作者：
Cuervo, Ana Maria