A Specific Epitope of Protein Inhibitor of Activated STAT3 Is Responsible for the Induction of Apoptosis in Rat Transformed Mast Cells

Abstract

Protein inhibitor of activated STAT3 (PIAS3) functions in vivo as a key molecule in suppressing the transcriptional activity of both microphthalmia transcription factor (MITF) and STAT3, two transcription factors that play a major role in the development, phenotypic expression, and survival of mast cells and melanocytes. In the present study we have investigated the role played by PIAS3 in the regulation of cell cycle in mast cells and melanocytes. We have characterized the biological role of a 23-aa domain derived from PIAS3 that induces apoptosis in these cells by inhibiting the transcriptional activity of both MITF and STAT3. This PIAS3 inhibitor peptide could serve as the beginning of an in depth study for the development of peptide inhibitors for MITF and STAT3.

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

“…It was therefore reasonable to postulate that PIAS3 and STAT3 might interact through similar domains. However, a previous report showed that an NH 2 -terminal fragment of mPIAS3, comprising amino acid positions 82 to 132, interacts with STAT3 in murine cell lines (15,29). We performed yeast two-hybrid analyses with the NH 2 terminal (amino acid positions 1-319) and the COOH terminal (amino acid positions 320-619) fragments of hPIAS3.…”

“…A few studies have addressed the effects of exogenous PIAS3 overexpression in cancer cells: (a) about 89% of glioblastoma samples were found to be PIAS3 negative and P-STAT3 positive and the ectopic expression of PIAS3 in a glioblastoma cell line caused the inhibition of the transcriptional activity of STAT3 (14); (b) overexpression of PIAS3 in melanoma and lung cancer cell lines inhibited cell growth and suppressed STAT3 activity (15,16); (c) overexpression of PIAS3 in v-Src-overexpressing tumor cells suppressed STAT3 target gene expression (17); (d) exogenous expression, mediated by infection with an adenovirus encoding kChaP/PIAS3β in prostate cancer cells, induced apoptosis and reduced growth of prostate tumor xenografts in nude mice (18). These studies indicate that PIAS3 can counteract the function of constitutively active STAT3.…”

A positive feedback loop between miR‐181b and STAT3 that affects Warburg effect in colon cancer via regulating PIAS3 expression

“…We demonstrated that miR‐181b directly bound to the PIAS3 3′UTR and inhibited the expression of PIAS3, and PIAS3 suppression contributed to the activation of STAT3. The proline, isoleucine, asparagine, isoleucine, threonine (PINIT) motif is one of several conserved domains of the PIAS family 37, 38. The PINIT domain allows nuclear translocation of PIAS337, 38 and it is known to promote STAT3‐PIAS3 interaction 39.…”

“…The proline, isoleucine, asparagine, isoleucine, threonine (PINIT) motif is one of several conserved domains of the PIAS family 37, 38. The PINIT domain allows nuclear translocation of PIAS337, 38 and it is known to promote STAT3‐PIAS3 interaction 39. A short stretch of 50 amino acids in the PINIT domain of PIAS3 (PIAS3 82‐132 ) can directly interact with STAT3 and down‐regulate STAT3‐dependent transcriptional activity 37, 38.…”

“…The PINIT domain allows nuclear translocation of PIAS337, 38 and it is known to promote STAT3‐PIAS3 interaction 39. A short stretch of 50 amino acids in the PINIT domain of PIAS3 (PIAS3 82‐132 ) can directly interact with STAT3 and down‐regulate STAT3‐dependent transcriptional activity 37, 38. The (His)(7) ‐PINIT domain (PIAS3 85‐272 ) alone is shown to specifically bind to STAT3 in a concentration‐dependent manner 39.…”