Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting.
Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting.
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DOI：
10.1007/s10555-017-9725-6
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Groden J
中科院分区：
文献类型：
--
作者：
Hankey W;Frankel WL;Groden J
APC基因中双等位基因突变的获得是大多数结直肠癌发展中的限速步骤，并且发生在最早的病变中。APC编码一种312 kDa的蛋白质，定位于多个亚细胞区室并执行多种功能。APC参与促进转录许可因子β-catenin破坏的细胞质复合物;消除该功能的APC突变触发经典WNT信号通路的组成性激活，这是几乎所有结直肠癌中发现的特征。通过负性调节经典WNT信号，APC抵消增殖，促进分化，促进凋亡，并抑制侵袭和肿瘤进展。APC通过与细胞核中的β-连环蛋白相互作用并抵消β-连环蛋白而进一步拮抗经典WNT信号传导。APC还通过独立于经典WNT信号传导的功能抑制结肠直肠上皮中的肿瘤起始和进展。APC调节有丝分裂纺锤体以促进正确的染色体分离，定位于细胞外周和细胞突起以建立细胞极性和适当的定向迁移，并通过直接与DNA相互作用来抑制DNA复制。APC中的突变通常是移码、插入或缺失，其引入过早终止密码子并导致产生缺乏其正常功能并具有致瘤特性的截短的APC蛋白。开发中用于治疗APC缺陷型肿瘤的治疗方法集中于抑制典型WNT信号传导，特别是通过途径中APC下游的靶标，或恢复野生型APC表达。
The acquisition of biallelic mutations in the APC gene is a rate-limiting step in the development of most colorectal cancers and occurs in the earliest lesions. APC encodes a 312-kDa protein that localizes to multiple subcellular compartments and performs diverse functions. APC participates in a cytoplasmic complex that promotes the destruction of the transcriptional licensing factor β-catenin; APC mutations that abolish this function trigger constitutive activation of the canonical WNT signaling pathway, a characteristic found in almost all colorectal cancers. By negatively regulating canonical WNT signaling, APC counteracts proliferation, promotes differentiation, facilitates apoptosis and suppresses invasion and tumor progression. APC further antagonizes canonical WNT signaling by interacting with and counteracting β-catenin in the nucleus. APC also suppresses tumor initiation and progression in the colorectal epithelium through functions that are independent of canonical WNT signaling. APC regulates the mitotic spindle to facilitate proper chromosome segregation, localizes to the cell periphery and cell protrusions to establish cell polarity and appropriate directional migration, and inhibits DNA replication by interacting directly with DNA. Mutations in APC are often frameshifts, insertions or deletions that introduce premature stop codons and lead to the production of truncated APC proteins that lack its normal functions and possess tumorigenic properties. Therapeutic approaches in development for the treatment of APC-deficient tumors are focused on the inhibition of canonical WNT signaling, especially through targets downstream of APC in the pathway, or on the restoration of wild-type APC expression.
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影响因子：
56.9
作者：
Behrens, J;Jerchow, BA;Birchmeier, W
通讯作者：
Birchmeier, W
各种人类截短的腺瘤性息肉病大肠杆菌同工型在控制β-蛋白 - - - - - - 钙蛋白活性和细胞增殖中）的共同作用。
影响因子：
3.7
作者：
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通讯作者：
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影响因子：
4.6
作者：
Andreu, P;Colnot, S;Romagnolo, B
通讯作者：
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影响因子：
11.4
作者：
BAEG, GH;MATSUMINE, A;AKIYAMA, T
通讯作者：
AKIYAMA, T
影响因子：
11.4
作者：
Aberle, H;Bauer, A;Kemler, R
通讯作者：
Kemler, R