NIPP1 is a ubiquitously expressed regulatory subunit of PP1. Its embryonic deletion in keratinocytes causes chronic sterile skin inflammation, epidermal hyperproliferation, and resistance to mutagens in adult mice. To explore the primary effects of NIPP1 deletion, we first examined hair cycle progression of NIPP1 skin knockouts (SKOs). The entry of the first hair cycle in the SKOs was delayed owing to prolonged quiescence of hair follicle stem cells. In contrast, the entry of the second hair cycle in the SKOs was advanced as a result of precocious activation of hair follicle stem cells. The epidermis of SKOs progressively accumulated senescent cells, and this cell-fate switch was accelerated by DNA damage. Primary keratinocytes from SKO neonates and human NIPP1-depleted HaCaT keratinocytes failed to proliferate and showed an increase in the expression of cell cycle inhibitors (p21, , and/or ) and senescence-associated-secretory-phenotype factors as well as in DNA damage (γH2AX and 53BP1). Our data demonstrate that the primary effect of NIPP1 deletion in keratinocytes is a cell cycle arrest and premature senescence that gradually progresse to chronic senescence and likely contribute to the decreased sensitivity of SKOs to mutagens.

中文翻译：

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角质形成细胞中胚胎 NIPP1 的缺失会引发成年小鼠的细胞周期停滞和过早衰老

NIPP1 是 PP1 普遍表达的调节亚基。它在角质形成细胞中的胚胎缺失会导致成年小鼠慢性无菌性皮肤炎症、表皮过度增殖和对诱变剂的抵抗力。为了探索 NIPP1 缺失的主要影响，我们首先检查了 NIPP1 皮肤敲除 (SKO) 的毛发周期进展。由于毛囊干细胞长时间静止，SKO 中第一个毛发周期的进入被延迟。相比之下，由于毛囊干细胞提前激活，SKO 中第二个毛发周期的进入提前。 SKO 的表皮逐渐积累衰老细胞，而 DNA 损伤加速了这种细胞命运的转变。来自 SKO 新生儿和人 NIPP1 耗尽的 HaCaT 角质形成细胞无法增殖，并显示细胞周期抑制剂（p21、和/或 ）和衰老相关分泌表型因子以及 DNA 损伤的表达增加（ γH2AX 和 53BP1)。我们的数据表明，角质形成细胞中 NIPP1 缺失的主要影响是细胞周期停滞和过早衰老，并逐渐进展为慢性衰老，并可能导致 SKO 对诱变剂的敏感性降低。