Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.
Epidermal Tissue Adapts to Restrain Progenitors Carrying Clonal p53 Mutations.
复制标题
DOI：
10.1016/j.stem.2018.08.017
复制
发表时间：
2018-11-01
期刊：
影响因子：
23.9
通讯作者：
Jones PH
中科院分区：
文献类型：
--
作者：
Murai K;Skrupskelyte G;Piedrafita G;Hall M;Kostiou V;Ong SH;Nagy T;Cagan A;Goulding D;Klein AM;Hall BA;Jones PH
老化的人体组织，如暴露在阳光下的表皮，积累了大量携带致癌突变的祖细胞。然而，大多数携带这种突变的祖细胞在正常组织中定殖并持续存在而不形成肿瘤。在这里，我们研究了组织水平上的约束克隆祖细胞的行为诱导一个单一的等位基因p53突变（Trp 53 R245 W; p53突变/wt），在正常人表皮和鳞状细胞癌，在转基因小鼠表皮。由于增强的增殖，p53 β/wt祖细胞最初胜过野生型细胞，但随后恢复到正常的动力学和稳态。生理剂量的紫外线加速短期扩张的p53 p53/wt克隆，但其频率下降，长期照射，可能是由于位移的紫外线诱导的突变体克隆具有更高的竞争力健身。这些结果表明，多种机制抑制p53 β/wt祖细胞的增殖，从而维持表皮的完整性。p53突变体的祖细胞在竞争中胜过野生型细胞，在正常表皮上定居表皮适应突变体克隆，慢慢地恢复正常低剂量的紫外线在短期内驱动p53突变体克隆的扩增长时间的紫外线照射产生的突变体克隆可能胜过p53突变体细胞正常人表皮含有p53突变体克隆，其中很少形成肿瘤。Murai等人在转基因小鼠模型中追踪p53突变体克隆在表皮上的定植，显示组织如何适应突变细胞，并揭示生理紫外线暴露的不同作用。
Aging human tissues, such as sun-exposed epidermis, accumulate a high burden of progenitor cells that carry oncogenic mutations. However, most progenitors carrying such mutations colonize and persist in normal tissue without forming tumors. Here, we investigated tissue-level constraints on clonal progenitor behavior by inducing a single-allele p53 mutation (Trp53R245W; p53∗/wt), prevalent in normal human epidermis and squamous cell carcinoma, in transgenic mouse epidermis. p53∗/wt progenitors initially outcompeted wild-type cells due to enhanced proliferation, but subsequently reverted toward normal dynamics and homeostasis. Physiological doses of UV light accelerated short-term expansion of p53∗/wt clones, but their frequency decreased with protracted irradiation, possibly due to displacement by UV-induced mutant clones with higher competitive fitness. These results suggest multiple mechanisms restrain the proliferation of p53∗/wt progenitors, thereby maintaining epidermal integrity. p53 mutant progenitors outcompete wild-type cells to colonize normal epidermis The epidermis adapts to the mutant clones, slowly returning toward normal Low-dose UV light drives p53 mutant clone expansion in the short term Prolonged UV exposure generates mutant clones that may outcompete p53 mutant cells Normal human epidermis harbors p53 mutant clones, very few of which form tumors. Murai et al. track p53 mutant clones as they colonize the epidermis in a transgenic mouse model showing how the tissue adapts to the mutant cells and uncovering distinct roles for physiological UV light exposure.
登录
查看更多内容
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
DOI：
10.1056/nejmoa1701719
发表时间：
2017-07-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Jaiswal S;Natarajan P;Silver AJ;Gibson CJ;Bick AG;Shvartz E;McConkey M;Gupta N;Gabriel S;Ardissino D;Baber U;Mehran R;Fuster V;Danesh J;Frossard P;Saleheen D;Melander O;Sukhova GK;Neuberg D;Libby P;Kathiresan S;Ebert BL
通讯作者：
Ebert BL
影响因子：
14.8
作者：
通讯作者：
--