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Sci. Signal., 15 February 2011
Vol. 4, Issue 160, p. ra9
[DOI: 10.1126/scisignal.2001426]

RESEARCH ARTICLES

MUC1-C Oncoprotein Promotes STAT3 Activation in an Autoinductive Regulatory Loop

Rehan Ahmad*, Hasan Rajabi*, Michio Kosugi, Maya Datt Joshi, Maroof Alam, Baldev Vasir, Takeshi Kawano{dagger}, Surender Kharbanda{ddagger}, and Donald Kufe§

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

* These authors contributed equally to this work.

{dagger} Present address: Jikei University School of Medicine, Tokyo 105-8461, Japan .

{ddagger} Present address: Genus Oncology, Boston, MA 02118, USA.

Abstract: Signal transducer and activator of transcription 3 (STAT3) is activated in human breast cancer and other malignancies. Mucin 1 (MUC1) is a heterodimeric cell surface glycoprotein that is overexpressed in human carcinomas and, like STAT3, promotes cell survival and induces transformation. We found that in breast cancer cells, the MUC1 carboxyl-terminal receptor subunit (MUC1-C) associates with the gp130–Janus-activated kinase 1 (JAK1)–STAT3 complex. The MUC1-C cytoplasmic domain interacted directly with JAK1 and STAT3, and MUC1-C was necessary for JAK1-mediated STAT3 activation. In turn, MUC1-C and activated STAT3 occupied the promoter of MUC1, and MUC1-C contributed to STAT3-mediated activation of MUC1 transcription. The MUC1-C inhibitor GO-201 blocked the MUC1-C interaction with STAT3, thereby decreasing MUC1-C and STAT3 occupancy on the MUC1 and STAT3 promoters and activation of STAT3 target genes, including MUC1 itself. These findings indicate that MUC1-C promotes STAT3 activation and that MUC1-C and STAT3 function in an autoinductive loop that may play a role in cancer cell survival.

§ To whom correspondence should be addressed. E-mail: donald_kufe{at}dfci.harvard.edu

Citation: R. Ahmad, H. Rajabi, M. Kosugi, M. D. Joshi, M. Alam, B. Vasir, T. Kawano, S. Kharbanda, D. Kufe, MUC1-C Oncoprotein Promotes STAT3 Activation in an Autoinductive Regulatory Loop. Sci. Signal. 4, ra9 (2011).

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