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MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1.

Brundage ME, Tandon P, Eaves DW, Williams JP, Miller SJ, Hennigan RH, Jegga A, Cripe TP, Ratner N - Oncogene (2014)

Bottom Line: Mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene are common in cancer and can cause resistance to therapy.RAD001 blocked MAF-mediated tumor growth, and MAF regulated the mTOR pathway through DEPTOR.MAPK inhibition with NF1 loss of function is predicted to show limited efficacy due to reactivation of mTOR signaling via MAF.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

ABSTRACT
Mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene are common in cancer and can cause resistance to therapy. Using transcriptome analysis we identified MAF as an NF1- regulated transcription factor and verified MAF regulation through RAS/MAPK/AP-1 signaling in malignant peripheral nerve sheath tumor (MPNST) cell lines. MAF was also downregulated in human MPNST. Acute re-expression of MAF promoted expression of glial differentiation markers in MPNST cells in vitro, decreased self-renewal of embryonic precursors and transiently affected tumor cell phenotypes in vitro by increasing MPNST cell death and reducing metabolic activity and anchorage-independent growth. Paradoxically, chronic MAF overexpression enhanced MPNST cell tumor growth in vivo, correlating with elevated pS6 in vitro and in vivo. RAD001 blocked MAF-mediated tumor growth, and MAF regulated the mTOR pathway through DEPTOR. MAPK inhibition with NF1 loss of function is predicted to show limited efficacy due to reactivation of mTOR signaling via MAF.

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NF1 mediated control of Ras-MAPK signaling: cross-talk with mTOR signaling through DEPTOR(A) In the absence of NF1, MAF expression is suppressed through a RAS/MAPK/AP-1 pathway. The transient effects of high MAF re-expression include an increase in cell death and decreases in SOX9, proliferation, and anchorage independent growth. (B) MAF also regulates DEPTOR, which negatively regulates TORC1 activity. TORC1 activity can be read-out by the activity of its substrates, such as the phosphorylation of S6 by S6K. In turn, S6K activity causes negative feedback resulting in the decreased phosphorylation of AKT. Our studies suggest that sustained lower levels of MAF expression in vivo increase TORC1 activity and enhance tumor growth. This enhanced TORC1 signaling renders tumors vulnerable to TORC1 inhibition with RAD001.
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Figure 9: NF1 mediated control of Ras-MAPK signaling: cross-talk with mTOR signaling through DEPTOR(A) In the absence of NF1, MAF expression is suppressed through a RAS/MAPK/AP-1 pathway. The transient effects of high MAF re-expression include an increase in cell death and decreases in SOX9, proliferation, and anchorage independent growth. (B) MAF also regulates DEPTOR, which negatively regulates TORC1 activity. TORC1 activity can be read-out by the activity of its substrates, such as the phosphorylation of S6 by S6K. In turn, S6K activity causes negative feedback resulting in the decreased phosphorylation of AKT. Our studies suggest that sustained lower levels of MAF expression in vivo increase TORC1 activity and enhance tumor growth. This enhanced TORC1 signaling renders tumors vulnerable to TORC1 inhibition with RAD001.

Mentions: Our data identify MAF as an NF1-regulated target gene downstream of the RAS effector pathway RAS/MAPK/AP-1 (Figure 9A). To our knowledge, MAF is the first cancer relevant NF1 target identified. There is previous evidence supporting the regulation of AP-1 activity by NF1 through a MAPK pathway in the ST88-14 MPNST cell line (35) and MAF was previously reported to be regulated by a MEK-ERK-FOS pathway in myeloma cell lines (40). This suggests that NF1 regulation of MAF may be relevant to other cell types and other cancers.


MAF mediates crosstalk between Ras-MAPK and mTOR signaling in NF1.

Brundage ME, Tandon P, Eaves DW, Williams JP, Miller SJ, Hennigan RH, Jegga A, Cripe TP, Ratner N - Oncogene (2014)

NF1 mediated control of Ras-MAPK signaling: cross-talk with mTOR signaling through DEPTOR(A) In the absence of NF1, MAF expression is suppressed through a RAS/MAPK/AP-1 pathway. The transient effects of high MAF re-expression include an increase in cell death and decreases in SOX9, proliferation, and anchorage independent growth. (B) MAF also regulates DEPTOR, which negatively regulates TORC1 activity. TORC1 activity can be read-out by the activity of its substrates, such as the phosphorylation of S6 by S6K. In turn, S6K activity causes negative feedback resulting in the decreased phosphorylation of AKT. Our studies suggest that sustained lower levels of MAF expression in vivo increase TORC1 activity and enhance tumor growth. This enhanced TORC1 signaling renders tumors vulnerable to TORC1 inhibition with RAD001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4127377&req=5

Figure 9: NF1 mediated control of Ras-MAPK signaling: cross-talk with mTOR signaling through DEPTOR(A) In the absence of NF1, MAF expression is suppressed through a RAS/MAPK/AP-1 pathway. The transient effects of high MAF re-expression include an increase in cell death and decreases in SOX9, proliferation, and anchorage independent growth. (B) MAF also regulates DEPTOR, which negatively regulates TORC1 activity. TORC1 activity can be read-out by the activity of its substrates, such as the phosphorylation of S6 by S6K. In turn, S6K activity causes negative feedback resulting in the decreased phosphorylation of AKT. Our studies suggest that sustained lower levels of MAF expression in vivo increase TORC1 activity and enhance tumor growth. This enhanced TORC1 signaling renders tumors vulnerable to TORC1 inhibition with RAD001.
Mentions: Our data identify MAF as an NF1-regulated target gene downstream of the RAS effector pathway RAS/MAPK/AP-1 (Figure 9A). To our knowledge, MAF is the first cancer relevant NF1 target identified. There is previous evidence supporting the regulation of AP-1 activity by NF1 through a MAPK pathway in the ST88-14 MPNST cell line (35) and MAF was previously reported to be regulated by a MEK-ERK-FOS pathway in myeloma cell lines (40). This suggests that NF1 regulation of MAF may be relevant to other cell types and other cancers.

Bottom Line: Mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene are common in cancer and can cause resistance to therapy.RAD001 blocked MAF-mediated tumor growth, and MAF regulated the mTOR pathway through DEPTOR.MAPK inhibition with NF1 loss of function is predicted to show limited efficacy due to reactivation of mTOR signaling via MAF.

View Article: PubMed Central - PubMed

Affiliation: Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

ABSTRACT
Mutations in the neurofibromatosis type 1 (NF1) tumor suppressor gene are common in cancer and can cause resistance to therapy. Using transcriptome analysis we identified MAF as an NF1- regulated transcription factor and verified MAF regulation through RAS/MAPK/AP-1 signaling in malignant peripheral nerve sheath tumor (MPNST) cell lines. MAF was also downregulated in human MPNST. Acute re-expression of MAF promoted expression of glial differentiation markers in MPNST cells in vitro, decreased self-renewal of embryonic precursors and transiently affected tumor cell phenotypes in vitro by increasing MPNST cell death and reducing metabolic activity and anchorage-independent growth. Paradoxically, chronic MAF overexpression enhanced MPNST cell tumor growth in vivo, correlating with elevated pS6 in vitro and in vivo. RAD001 blocked MAF-mediated tumor growth, and MAF regulated the mTOR pathway through DEPTOR. MAPK inhibition with NF1 loss of function is predicted to show limited efficacy due to reactivation of mTOR signaling via MAF.

Show MeSH
Related in: MedlinePlus