SOCS1, a novel interaction partner of p53 controlling oncogene-induced senescence
Frédérick A Mallette1, Viviane Calabrese, Subburaj Ilangumaran
1Département de Biochimie, Université de Montréal, Québec, Canada.
Abstract:
Members of the signal transducers and activators of transcription (STATs) family of proteins, which connect cytokine signaling to activation of transcription, are frequently activated in human cancers. Suppressors of cytokine signaling (SOCS) are transcriptional targets of activated STAT proteins that negatively control STAT signaling. SOCS1 expression is silenced in multiple human cancers suggesting a tumor suppressor role for this protein. However, SOCS1 not only regulates STAT signaling but can also localize to the nucleus and directly interact with the p53 tumor suppressor through its central SH2 domain. Furthermore, SOCS1 contributes to p53 activation and phosphorylation on serine 15 by forming a ternary complex with ATM or ATR. Through this mechanism SOCS1 regulates the process of oncogene-induced senescence, which is a very important tumor suppressor response. A mutant SOCS1 lacking the SOCS box cannot interact with ATM/ATR, stimulate p53 or induce the senescence phenotype, suggesting that the SOCS box recruits DNA damage activated kinases to its interaction partners bound to its SH2 domain. Proteomic analysis of SOCS1 interaction partners revealed other potential targets of SOCS1 in the DNA damage response. These newly discovered functions of SOCS1 help to explain the increased susceptibility of Socs1 null mice to develop cancer as well as their propensity to develop autoimmune diseases. Consistently, we found that mice lacking SOCS1 displayed defects in the regulation of p53 target genes including Mdm2, Pmp22, PUMA and Gadd45a. The involvement of SOCS1 in p53 activation and the DNA damage response defines a novel tumor suppressor pathway and intervention point for future cancer therapeutics.
Insights
Suppressor of cytokine signaling 1 (SOCS1) acts as a tumor suppressor by regulating p53 activation and DNA damage response. SOCS1 deficiency leads to cancer and autoimmune diseases in mice.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Signal transducers and activators of transcription (STATs) proteins are crucial in cytokine signaling and are often activated in human cancers.
- Suppressors of cytokine signaling (SOCS) proteins, including SOCS1, are transcriptional targets of STATs and negatively regulate STAT signaling.
- SOCS1 silencing in cancers suggests a tumor suppressor role, but its functions extend beyond STAT regulation.
Purpose of the Study:
- To investigate the novel tumor suppressor functions of SOCS1 beyond its role in STAT signaling.
- To elucidate the mechanism by which SOCS1 interacts with the p53 tumor suppressor and influences DNA damage response.
- To understand the implications of SOCS1's function in cancer and autoimmune disease pathogenesis.
Main Methods:
- Investigated SOCS1's nuclear localization and interaction with p53.
- Utilized mutant SOCS1 lacking the SOCS box to assess its role in ATM/ATR interaction and p53 activation.
- Performed proteomic analysis to identify SOCS1 interaction partners in DNA damage response.
- Examined p53 target gene regulation in Socs1 null mice.
Main Results:
- SOCS1 directly interacts with p53 and enhances its activation and phosphorylation via ATM/ATR.
- The SOCS box of SOCS1 is essential for recruiting DNA damage kinases to facilitate p53 activation and senescence induction.
- Proteomic analysis identified novel SOCS1 targets involved in DNA damage response.
- Socs1 null mice exhibit impaired regulation of p53 target genes (Mdm2, Pmp22, PUMA, Gadd45a) and increased susceptibility to cancer and autoimmune diseases.
Conclusions:
- SOCS1 functions as a novel tumor suppressor by mediating p53 activation and DNA damage response.
- The interaction of SOCS1 with ATM/ATR and p53 represents a critical pathway for tumor suppression and maintaining genomic stability.
- SOCS1's multifaceted role highlights its potential as a therapeutic target for cancer and autoimmune diseases.
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