γ-Catenin stabilizes β-catenin and induces Tcf/Lel reporter activity through a mechanism that requires armadillo repeats but not the activation domain of γ-catenin

Heat shock factor (HSF) activates transcription in response to cellular stress. Human HSF1 has a central regulatory domain which can repress the activity of its activation domains at the control temperature and render them heat shock inducible. To determine whether the regulatory domain works in tandem with specific features of the HSF1 transcriptional activation domains, we first used deletion and point mutagenesis to define these activation domains. One of the activation domains can be reduced to just 20 amino acids. A GAL4 fusion protein containing the HSF 1 regulatory domain and this 20-amino-acid activation domain is repressed at the control temperature but potently activates transcription in response to heat shock. No specific amino acids in this activation domain are required for response to the regulatory domain; in particular, none of the potentially phosphorylated serine and threonine residues are required for heat induction, implying that heat-induced phosphorylation of the transcriptional activation domains is not required for induction. The regulatory domain is able to confer heat responsiveness to an otherwise completely heterologous chimeric activator that contains a portion of the VP16 activation domain, suggesting that the regulatory domain can sense heat in the absence of other portions of HSF1.

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NT157 Inhibits HCC Migration via Downregulating the STAT3/Jab1 Signaling Pathway

Technology in Cancer Research & Treatment ◽

10.1177/15330338211027916 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110279

Author(s):

SiZhe Yu ◽

Yu Wang ◽

KeJia Lv ◽

Jia Hou ◽

WenYuan Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Lines ◽

Lung Metastasis ◽

Carcinoma Cell ◽

Binding Protein ◽

Signal Transducer ◽

Activation Domain ◽

Carcinoma Cell Lines ◽

Hepatocellular Carcinoma Cell ◽

Transcription 3

Purpose: The high fatality-to-case ratio of hepatocellular carcinoma is directly related to metastasis. The signal transducer and activator of transcription-3 is a key mediator of the cytokine and growth factor signaling pathways and drives the transcription of genes responsible for cancer-associated phenotypes. However, so far, no specific inhibitor for signal transducer and activator of transcription-3 has been used in clinical practice. Therefore, targeting the signal transducer and activator of transcription-3 for cancer therapy is highly desired to improve outcomes in patients with hepatocellular carcinoma. Experimental Design: Using the small-molecule inhibitor NT157, the effect of signal transducer and activator of transcription-3 inhibition on cell migration was tested in hepatocellular carcinoma cell lines and a lung metastasis model of the disease. Results: NT157 significantly inhibited the migration of hepatocellular carcinoma cell lines in vitro and lung metastasis of hepatocellular carcinoma in vivo. Mechanistically, it inhibited the phospho-signal transducer and activator of transcription-3 in a dose- and time-dependent manner. Furthermore, NT157 treatment suppressed the c-Jun activation domain-binding protein-1 levels in the nucleus but no significant decrease was observed in its expression in the cytoplasm. Finally, high mRNA expression levels of signal transducer and activator of transcription-3 and c-Jun activation domain-binding protein-1 in hepatocellular carcinoma were associated with significantly low survival rates. Conclusion: NT157 inhibits hepatocellular carcinoma migration and metastasis by downregulating the signal transducer and activator of transcription-3/c-Jun activation domain-binding protein-1 signaling pathway and targeting it may serve as a novel therapeutic strategy for the clinical management of hepatocellular carcinoma in the future.

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