Menin determines K-RAS proliferative outputs in endocrine cells

Chester E. Chamberlain, David W. Scheel, Kathleen McGlynn, Hail Kim, Takeshi Miyatsuka, Juehu Wang, Vinh Nguyen, Shuhong Zhao, Anastasia Mavropoulos, Aswin G. Abraham, Eric O'Neill, Gregory M. Ku, Melanie H. Cobb, Gail R. Martin, Michael S. German

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Endocrine cell proliferation fluctuates dramatically in response to signals that communicate hormone demand. The genetic alterations that override these controls in endocrine tumors often are not associated with oncogenes common to other tumor types, suggesting that unique pathways govern endocrine proliferation. Within the pancreas, for example, activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas but are never found in pancreatic endocrine tumors. Therefore, we asked how cellular context impacts K-RAS signaling. We found that K-RAS paradoxically suppressed, rather than promoted, growth in pancreatic endocrine cells. Inhibition of proliferation by K-RAS depended on antiproliferative RAS effector RASSF1A and blockade of the RAS-activated proproliferative RAF/ MAPK pathway by tumor suppressor menin. Consistent with this model, a glucagon-like peptide 1 (GLP1) agonist, which stimulates ERK1/2 phosphorylation, did not affect endocrine cell proliferation by itself, but synergistically enhanced proliferation when combined with a menin inhibitor. In contrast, inhibition of MAPK signaling created a synthetic lethal interaction in the setting of menin loss. These insights suggest potential strategies both for regenerating pancreatic β cells for people with diabetes and for targeting menin-sensitive endocrine tumors.

Original languageEnglish (US)
Pages (from-to)4093-4101
Number of pages9
JournalJournal of Clinical Investigation
Volume124
Issue number9
DOIs
StatePublished - Sep 2 2014

Fingerprint

Endocrine Cells
Neoplasms
Oncogenes
Cell Proliferation
Glucagon-Like Peptide 1
Pancreas
Phosphorylation
Hormones
Mutation
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Chamberlain, C. E., Scheel, D. W., McGlynn, K., Kim, H., Miyatsuka, T., Wang, J., ... German, M. S. (2014). Menin determines K-RAS proliferative outputs in endocrine cells. Journal of Clinical Investigation, 124(9), 4093-4101. https://doi.org/10.1172/JCI69004

Menin determines K-RAS proliferative outputs in endocrine cells. / Chamberlain, Chester E.; Scheel, David W.; McGlynn, Kathleen; Kim, Hail; Miyatsuka, Takeshi; Wang, Juehu; Nguyen, Vinh; Zhao, Shuhong; Mavropoulos, Anastasia; Abraham, Aswin G.; O'Neill, Eric; Ku, Gregory M.; Cobb, Melanie H.; Martin, Gail R.; German, Michael S.

In: Journal of Clinical Investigation, Vol. 124, No. 9, 02.09.2014, p. 4093-4101.

Research output: Contribution to journalArticle

Chamberlain, CE, Scheel, DW, McGlynn, K, Kim, H, Miyatsuka, T, Wang, J, Nguyen, V, Zhao, S, Mavropoulos, A, Abraham, AG, O'Neill, E, Ku, GM, Cobb, MH, Martin, GR & German, MS 2014, 'Menin determines K-RAS proliferative outputs in endocrine cells', Journal of Clinical Investigation, vol. 124, no. 9, pp. 4093-4101. https://doi.org/10.1172/JCI69004
Chamberlain CE, Scheel DW, McGlynn K, Kim H, Miyatsuka T, Wang J et al. Menin determines K-RAS proliferative outputs in endocrine cells. Journal of Clinical Investigation. 2014 Sep 2;124(9):4093-4101. https://doi.org/10.1172/JCI69004
Chamberlain, Chester E. ; Scheel, David W. ; McGlynn, Kathleen ; Kim, Hail ; Miyatsuka, Takeshi ; Wang, Juehu ; Nguyen, Vinh ; Zhao, Shuhong ; Mavropoulos, Anastasia ; Abraham, Aswin G. ; O'Neill, Eric ; Ku, Gregory M. ; Cobb, Melanie H. ; Martin, Gail R. ; German, Michael S. / Menin determines K-RAS proliferative outputs in endocrine cells. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 9. pp. 4093-4101.
@article{bb6762867b5146739e8c088f1357f525,
title = "Menin determines K-RAS proliferative outputs in endocrine cells",
abstract = "Endocrine cell proliferation fluctuates dramatically in response to signals that communicate hormone demand. The genetic alterations that override these controls in endocrine tumors often are not associated with oncogenes common to other tumor types, suggesting that unique pathways govern endocrine proliferation. Within the pancreas, for example, activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas but are never found in pancreatic endocrine tumors. Therefore, we asked how cellular context impacts K-RAS signaling. We found that K-RAS paradoxically suppressed, rather than promoted, growth in pancreatic endocrine cells. Inhibition of proliferation by K-RAS depended on antiproliferative RAS effector RASSF1A and blockade of the RAS-activated proproliferative RAF/ MAPK pathway by tumor suppressor menin. Consistent with this model, a glucagon-like peptide 1 (GLP1) agonist, which stimulates ERK1/2 phosphorylation, did not affect endocrine cell proliferation by itself, but synergistically enhanced proliferation when combined with a menin inhibitor. In contrast, inhibition of MAPK signaling created a synthetic lethal interaction in the setting of menin loss. These insights suggest potential strategies both for regenerating pancreatic β cells for people with diabetes and for targeting menin-sensitive endocrine tumors.",
author = "Chamberlain, {Chester E.} and Scheel, {David W.} and Kathleen McGlynn and Hail Kim and Takeshi Miyatsuka and Juehu Wang and Vinh Nguyen and Shuhong Zhao and Anastasia Mavropoulos and Abraham, {Aswin G.} and Eric O'Neill and Ku, {Gregory M.} and Cobb, {Melanie H.} and Martin, {Gail R.} and German, {Michael S.}",
year = "2014",
month = "9",
day = "2",
doi = "10.1172/JCI69004",
language = "English (US)",
volume = "124",
pages = "4093--4101",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "9",

}

TY - JOUR

T1 - Menin determines K-RAS proliferative outputs in endocrine cells

AU - Chamberlain, Chester E.

AU - Scheel, David W.

AU - McGlynn, Kathleen

AU - Kim, Hail

AU - Miyatsuka, Takeshi

AU - Wang, Juehu

AU - Nguyen, Vinh

AU - Zhao, Shuhong

AU - Mavropoulos, Anastasia

AU - Abraham, Aswin G.

AU - O'Neill, Eric

AU - Ku, Gregory M.

AU - Cobb, Melanie H.

AU - Martin, Gail R.

AU - German, Michael S.

PY - 2014/9/2

Y1 - 2014/9/2

N2 - Endocrine cell proliferation fluctuates dramatically in response to signals that communicate hormone demand. The genetic alterations that override these controls in endocrine tumors often are not associated with oncogenes common to other tumor types, suggesting that unique pathways govern endocrine proliferation. Within the pancreas, for example, activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas but are never found in pancreatic endocrine tumors. Therefore, we asked how cellular context impacts K-RAS signaling. We found that K-RAS paradoxically suppressed, rather than promoted, growth in pancreatic endocrine cells. Inhibition of proliferation by K-RAS depended on antiproliferative RAS effector RASSF1A and blockade of the RAS-activated proproliferative RAF/ MAPK pathway by tumor suppressor menin. Consistent with this model, a glucagon-like peptide 1 (GLP1) agonist, which stimulates ERK1/2 phosphorylation, did not affect endocrine cell proliferation by itself, but synergistically enhanced proliferation when combined with a menin inhibitor. In contrast, inhibition of MAPK signaling created a synthetic lethal interaction in the setting of menin loss. These insights suggest potential strategies both for regenerating pancreatic β cells for people with diabetes and for targeting menin-sensitive endocrine tumors.

AB - Endocrine cell proliferation fluctuates dramatically in response to signals that communicate hormone demand. The genetic alterations that override these controls in endocrine tumors often are not associated with oncogenes common to other tumor types, suggesting that unique pathways govern endocrine proliferation. Within the pancreas, for example, activating mutations of the prototypical oncogene KRAS drive proliferation in all pancreatic ductal adenocarcimomas but are never found in pancreatic endocrine tumors. Therefore, we asked how cellular context impacts K-RAS signaling. We found that K-RAS paradoxically suppressed, rather than promoted, growth in pancreatic endocrine cells. Inhibition of proliferation by K-RAS depended on antiproliferative RAS effector RASSF1A and blockade of the RAS-activated proproliferative RAF/ MAPK pathway by tumor suppressor menin. Consistent with this model, a glucagon-like peptide 1 (GLP1) agonist, which stimulates ERK1/2 phosphorylation, did not affect endocrine cell proliferation by itself, but synergistically enhanced proliferation when combined with a menin inhibitor. In contrast, inhibition of MAPK signaling created a synthetic lethal interaction in the setting of menin loss. These insights suggest potential strategies both for regenerating pancreatic β cells for people with diabetes and for targeting menin-sensitive endocrine tumors.

UR - http://www.scopus.com/inward/record.url?scp=84907009884&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907009884&partnerID=8YFLogxK

U2 - 10.1172/JCI69004

DO - 10.1172/JCI69004

M3 - Article

VL - 124

SP - 4093

EP - 4101

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

ER -