Nephron progenitor cells surround around the ureteric bud tips (UB) and inductively interact with the UB to originate nephrons, the basic units of renal function. This process is determined by the internal balance between self-renewal and consumption of the nephron progenitor cells, which is depending on the complicated regulation networks. It has been reported that Zeb1 regulates the proliferation of mesenchymal cells in mouse embryos. However, the role of Zeb1 in nephrons generation is not clear, especially in metanephric mesenchyme (MM). Here, we detected cell proliferation, apoptosis and migration in MM cells by EdU assay, flow cytometry assay and wound healing assay, respectively. Meanwhile, Western and RT-PCR were used to measure the expression level of Zeb1 and Six2 in MM cells and developing kidney. Besides, the dual-luciferase assay was conducted to study the molecular relationship between Zeb1 and Six2. We found that knock-down of Zeb1 decreased cell proliferation, migration and promoted cell apoptosis in MM cells and Zeb1 overexpression leaded to the opposite data. Western-blot and RT-PCR results showed that knock-down of Zeb1 decreased the expression of Six2 in MM cells and Zeb1 overexpression contributed to the opposite results. Similarly, Zeb1 promoted Six2 promoter reporter activity in luciferase assays. However, double knock-down of Zeb1 and Six2 did not enhance the apoptosis of MM cells compared with control cells. Nevertheless, double silence of Zeb1 and Six2 repressed cell proliferation. In addition, we also found that Zeb1 and Six2 had an identical pattern in distinct developing phases of embryonic kidney. These results indicated that there may exist a complicated regulation network between Six2 and Zeb1. Together, we demonstrate Zeb1 promotes proliferation and apoptosis and inhibits the migration of MM cells, in association with Six2.

Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. Conversely, deficiency or depletion of TTC36 results in enhanced STK33-mediated HPD T382 phosphorylation and binding of PELI1 to HPD and subsequent PELI1-mediated HPD downregulation. Ttc36−/− mice have reduced HPD expression in the liver and exhibit tyrosinemia, damage to hippocampal neurons, and deficits of learning and memory. These findings reveal a previously unknown regulation of HPD expression and highlight the physiological significance of TTC36-STK33-PELI1-regulated HPD expression in tyrosinemia and tyrosinemia-associated neurological disorders.

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Accumulating evidence indicates that hotspot p53 mutants have gain-of-function in promoting cell migration and tumor metastasis. However, the molecular mechanisms are not completely understood. Here, we show that a hotspot mutation, p53-R273H, promotes non-small cell lung cancer (NSCLC) cell migration and upregulates the mRNA and protein expression of neuraminidase-1 (NEU1), a sialidase involved in cell proliferation, cell migration and tumorigenesis. Silencing of NEU1 leads to upregulation of integrin β4 which significantly inhibits NSCLC cell migration induced by p53-R273H. Mechanistically, p53-R273H promotes NEU1 transcription via activation of AKT signaling. Importantly, NEU1 expression is upregulated in human NSCLC samples harboring mutant p53 and is associated with poor clinical outcome. Overall, this study highlights an important role of NEU1 in p53-R273H-induced NSCLC cell migration and provides a potential target for NSCLC diagnosis and treatment.

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