A new chemotherapeutic drug was identified that targets the TGF beta signaling p

Question

A new chemotherapeutic drug was identified that targets the TGF beta signaling pathway leading to a decrease in the transcription of the gene Pal - 1. Researchers trying to identify the drug?s mechanism of action performed a series of experiments with the results outlined below. In the presence of the drug... ChIP immunopreciptation analysis showed that the R - Smad / Co - Smad complex never bound to the transcriptional activation site Immunofluorescent analysis showed that the R - smad / Co - Smad complex never enters the nucleus, however nuclear import is unaffected R - Smad is phosphorlated at the three C - terminal Serine residues. R - Smad binds Co - Smad From these results, please give the best explanation of how the drug is affecting TGF beta signaling.

Explanation / Answer

PAI-1 is an inhibitor of plasminogen activator that works through the TGF-beta signaling via smad (R-smad/Co-smad) proteins which are typically localized into the nucleus binds with PAI-1 gene and promotes its transcription.

But, in your case, the therapeutic drug might inhibit the smad complex co-localization into the nucleus. So that, PAI-1 is not able to transcribe since, R-smad/Co-smad complex is not readily available to activate its gene expression. One more thing is that the phosphorylation of R-smad can lead to form a complex with the Co-smad that is normal with your drug. But its entry into the nucleus is inhibited.

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