Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75235.
Department of Molecular Medicine, Cornell University College of Veterinary Medicine, Ithaca, NY 14853.
Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2205201119. doi: 10.1073/pnas.2205201119. Epub 2022 Sep 6.
P53 is a widely studied tumor suppressor that plays important roles in cell-cycle regulation, cell death, and DNA damage repair. P53 is found throughout metazoans, even in invertebrates that do not develop malignancies. The prevailing theory for why these invertebrates possess a tumor suppressor is that P53 originally evolved to protect the germline of early metazoans from genotoxic stress such as ultraviolet radiation. This theory is largely based upon functional data from only three invertebrates, omitting important groups of animals including flatworms. Previous studies in the freshwater planarian flatworm suggested that flatworm P53 plays an important role in stem cell maintenance and skin production, but these studies did not directly test for any tumor suppressor functions. To better understand the function of P53 homologs across diverse flatworms, we examined the function of two different P53 homologs in the parasitic flatworm . The first P53 homolog () is orthologous to P53() and human TP53 and regulates flatworm stem cell maintenance and skin production. The second P53 homolog () is a parasite-specific paralog that is conserved across parasitic flatworms and is required for the normal response to genotoxic stress in . We then found that does not seem to play any role in the planarian response to genotoxic stress. The existence of this parasite-specific paralog that bears a tumor suppressor-like function in parasitic flatworms implies that the ability to respond to genotoxic stress in parasitic flatworms may have arisen from convergent evolution.
P53 是一种广泛研究的肿瘤抑制因子，在细胞周期调控、细胞死亡和 DNA 损伤修复中发挥重要作用。P53 存在于后生动物中，甚至在不发生恶性肿瘤的无脊椎动物中也存在。这些无脊椎动物拥有肿瘤抑制因子的流行理论是，P53 最初是为了保护后生动物的生殖细胞免受如紫外线辐射等遗传毒性应激的影响而进化而来的。这一理论主要基于来自仅三种无脊椎动物的功能数据，忽略了包括扁形动物在内的重要动物群体。先前在淡水扁形动物中的研究表明，扁形动物 P53 在干细胞维持和皮肤生成中发挥重要作用，但这些研究并未直接测试任何肿瘤抑制功能。为了更好地了解不同扁形动物中 P53 同源物的功能，我们研究了寄生性扁形动物中的两种不同 P53 同源物的功能。第一个 P53 同源物（）与 P53()和人类 TP53 同源，调节扁形动物干细胞维持和皮肤生成。第二个 P53 同源物（）是一种寄生虫特异性的旁系同源物，在寄生性扁形动物中保守，是对寄生虫中遗传毒性应激做出正常反应所必需的。然后我们发现似乎在扁形动物对遗传毒性应激的反应中不起任何作用。这种寄生虫特异性的旁系同源物具有肿瘤抑制因子样功能，存在于寄生性扁形动物中，这意味着寄生虫中对遗传毒性应激做出反应的能力可能是来自趋同进化。
