Article

Zhu, J., Blenis, J. & Yuan, J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc. Natl Acad. Sci. USA 105, 6584-6589

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2008; 105(18):6584-9. DOI: 10.1073/pnas.0802785105
Source: PubMed

ABSTRACT

Mad1, a member of the Myc/Max/Mad family, suppresses Myc-mediated transcriptional activity by competing with Myc for heterodimerization with its obligatory partner, Max. The expression of Mad1 suppresses Myc-mediated cell proliferation and transformation. The levels of Mad1 protein are generally low in many human cancers, and Mad1 protein has a very short half-life. However, the mechanism that regulates the turnover of Mad1 protein is poorly understood. In this study, we showed that Mad1 is a substrate of p90 ribosomal kinase (RSK) and p70 S6 kinase (S6K). Both RSK and S6K phosphorylate serine 145 of Mad1 upon serum or insulin stimulation. Ser-145 phosphorylation of Mad1 accelerates the ubiquitination and degradation of Mad1 through the 26S proteasome pathway, which in turn promotes the transcriptional activity of Myc. Our study provides a direct link between the growth factor signaling pathways regulated by PI3 kinase/Akt and MAP kinases with Myc-mediated transcription.

Download full-text

Full-text

Available from: John Blenis, Sep 22, 2014
  • Source
    • "stimulated cell growth and proliferation and resulted in reduced thymic cellularity [60] [167]. Although the physiological relevance of these studies is not clear, MAD1 degradation is stimulated by its phosphorylation by p90 ribosomal kinase (RSK) and p70 S6 kinase [168], key downstream effectors of AKT signaling that control ribosomal biogenesis and protein translation [169], and therefore raises the possibility that the balance between MYC and MAD1 controls a cell growth/size checkpoint that governs progression through the cell cycle. Similarly, overexpression of MAD1 in U937 monocytes led to decreased cell size and proliferation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The MYC family of proteins play essential roles in embryonic development and in oncogenesis. Efforts over the past 30years to define the transcriptional activities of MYC and how MYC functions to promote proliferation have produced evolving models of MYC function. One picture that has emerged of MYC and its partner protein MAX is of a transcription factor complex with a seemingly unique ability to stimulate the transcription of genes that are epigenetically poised for transcription and to amplify the transcription of actively transcribed genes. During lymphocyte activation, MYC is upregulated and stimulates a pro-proliferative program in part through the upregulation of a wide variety of metabolic effector genes that facilitate cell growth and cell cycle progression. MYC upregulation simultaneously sensitizes cells to apoptosis and activated lymphocytes and lymphoma cells have prosurvival attributes that allow MYC-driven proliferation to prevail. For example, the MAX-interacting protein MNT is upregulated in activated lymphocytes and was found to protect lymphocytes from MYC-dependent apoptosis. Here we review the activities of MYC, MNT and other MAX interacting proteins in the setting of T and B cell activation and oncogenesis. Myc proteins in cell biology and pathology.
    Full-text · Article · Apr 2014 · Biochimica et Biophysica Acta
  • Source
    • "(It is worth noting here that higher doses of rapamycin can inhibit both S6K and 4E-BP1 and, therefore, do not always discriminate between different mTOR functions in every study reported.) It is possible that activation of the S6-kinase by mTOR could additionally have a positive effect on MYC-mediated transcription through the phosphorylation and degradation of the MYC inhibitor, MAD1,84 but in terms of 4E-BP1 function, it is interesting to note that the activity of eIF4E has been previously reported to rescue cells from MYC-induced apoptosis.85 We found that inhibition of the PI3K/AKT/mTOR signaling pathway in BL cells decreased the expression of both c-MYC and MCL-1 (a prosurvival member of the BCL-2 family). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Burkitt's lymphoma (BL) is an aggressive disorder associated with extremely high rates of cell proliferation tempered by high levels of apoptosis. Despite the high levels of cell death, the net effect is one of rapid tumor growth. The tumor arises within the germinal centers of secondary lymphoid tissues and is identifiable by translocation of the c-MYC gene into the immunoglobulin gene loci, resulting in deregulation of the proto-oncogene. Many of the major players involved in determining the development of BL have been characterized in human BL cell lines or in mouse models of MYC-driven lymphomagenesis. Both systems have been useful so far in characterizing the role of tumor suppressor genes (for example, p53), prosurvival signaling pathways, and members of the B-cell lymphoma-2 family of apoptosis regulators in determining the fate of c-MYC overexpressing B-cells, and ultimately in regulating lymphoma development. Signaling through phosphoinositide (PI)3-kinase stands out as being critical for BL cell survival. Recurrent mutations in ID3 or TCF3 (E2A) that promote signaling through PI3-kinase have recently been identified in human BL samples, and new therapeutic strategies based on coordinately targeting both the prosurvival factor, B-cell lymphoma-XL, and the PI3-kinase/AKT/mammalian target of rapamycin (mTOR) signaling pathway to synergistically induced BL apoptosis have been proposed. Now, engineering both constitutive c-MYC expression and PI3-kinase activity, specifically in murine B-cells undergoing the germinal center reaction, has revealed that there is synergistic cooperation between c-MYC and PI3-kinase during BL development. The resulting tumors phenocopy the human malignancy, and acquire tertiary mutations also present in human tumors. This model may, therefore, prove useful in further studies to identify functionally relevant mutational events necessary for BL pathogenesis. This review discusses these cooperating interactions, the possible influence of BL tumor-associated viruses, and highlights potential new opportunities for therapeutic intervention.
    Full-text · Article · Jan 2014 · Cancer Management and Research
  • Source
    • "stimulated cell growth and proliferation and resulted in reduced thymic cellularity [60] [167]. Although the physiological relevance of these studies is not clear, MAD1 degradation is stimulated by its phosphorylation by p90 ribosomal kinase (RSK) and p70 S6 kinase [168], key downstream effectors of AKT signaling that control ribosomal biogenesis and protein translation [169], and therefore raises the possibility that the balance between MYC and MAD1 controls a cell growth/size checkpoint that governs progression through the cell cycle. Similarly, overexpression of MAD1 in U937 monocytes led to decreased cell size and proliferation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The MYC family of proteins play essential roles in embryonic development and in oncogenesis. Efforts over the past 30 years to define the transcriptional activities of MYC and how MYC functions to promote proliferation have produced evolving models of MYC function. One picture that has emerged of MYC and its partner protein MAX is of a transcription factor complex with a seemingly unique ability to stimulate the transcription of genes that are epigenetically poised for transcription and to amplify the transcription of actively transcribed genes. During lymphocyte activation, MYC is upregulated and stimulates a pro-proliferative program in part through the upregulation of a wide variety of metabolic effector genes that facilitate cell growth and cell cycle progression. MYC upregulation simultaneously sensitizes cells to apoptosis and activated lymphocytes and lymphoma cells have prosurvival attributes that allow MYC-driven proliferation to prevail. For example, the MAX-interacting protein MNT is upregulated in activated lymphocytes and was found to protect lymphocytes from MYC-dependent apoptosis. Here we review the activities of MYC, MNT and other MAX interacting proteins in the setting of T and B cell activation and oncogenesis. Myc proteins in cell biology and pathology
    Full-text · Article · Jan 2014 · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Show more