title: MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1.
abstract: Signaling through RAS/MAP kinase pathway is central to biology. ERK has long been perceived as the only substrate for MEK. Here, we report that HSF1, the master regulator of the proteotoxic stress response, is a new MEK substrate. Beyond mediating cell-environment interactions, the MEK-HSF1 regulation impacts malignancy. In tumor cells, MEK blockade inactivates HSF1 and thereby provokes proteomic chaos, presented as protein destabilization, aggregation, and, strikingly, amyloidogenesis. Unlike their non-transformed counterparts, tumor cells are particularly susceptible to proteomic perturbation and amyloid induction. Amyloidogenesis is tumor suppressive, reducing in vivo melanoma growth and contributing to the potent anti-neoplastic effects of proteotoxic stressors. Our findings unveil a key biological function of the oncogenic RAS-MEK signaling in guarding proteostasis and suppressing amyloidogenesis. Thus, proteomic instability is an intrinsic feature of malignant state, and disrupting the fragile tumor proteostasis to promote amyloidogenesis may be a feasible therapeutic strategy.
authors: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA; Graduate Programs, Department of Molecular and Biomedical Sciences, The University of Maine, 5735 Hitchner Hall, Orono, ME 04469, USA.
authors: Zijian
authors: Z
authors: Tang
authors: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors: Siyuan
authors: S
authors: Dai
authors: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors: Yishu
authors: Y
authors: He
authors: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors: Rosalinda A
authors: RA
authors: Doty
authors: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors: Leonard D
authors: LD
authors: Shultz
authors: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors: Stephen Byers
authors: SB
authors: Sampson
authors: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA. Electronic address: chengkai.dai@jax.org.
authors: Chengkai
authors: C
authors: Dai
mesh_terms: D000682:Amyloid / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D000076249:Heat Shock Transcription Factors; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D066329:Protein Aggregates; D055550:Protein Stability; D020543:Proteome / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D000682:Amyloid; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D066329:Protein Aggregates; D020543:Proteome; D014157:Transcription Factors; D020929:Mitogen-Activated Protein Kinase Kinases