Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors

Thomas A. Milne, Christina M. Hughes, Ricardo Lloyd, Zhaohai Yang, Orit Rozenblatt-Rosen, Yali Dou, Robert W. Schnepp, Cynthia Krankel, Virginia A. LiVolsi, Denise Gibbs, Xianxin Hua, Robert G. Roeder, Matthew Meyerson, Jay L. Hess

Research output: Contribution to journalArticle

314 Citations (Scopus)

Abstract

Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.

Original languageEnglish (US)
Pages (from-to)749-754
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number3
DOIs
StatePublished - Jan 18 2005

Fingerprint

Multiple Endocrine Neoplasia
Multiple Endocrine Neoplasia Type 1
Cyclin-Dependent Kinases
Leukemia
Myeloid-Lymphoid Leukemia Protein
Pituitary Neoplasms
Islets of Langerhans
Genetic Promoter Regions
Hyperplasia
Neoplasms
Down-Regulation
Mutation
Growth
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Milne, Thomas A. ; Hughes, Christina M. ; Lloyd, Ricardo ; Yang, Zhaohai ; Rozenblatt-Rosen, Orit ; Dou, Yali ; Schnepp, Robert W. ; Krankel, Cynthia ; LiVolsi, Virginia A. ; Gibbs, Denise ; Hua, Xianxin ; Roeder, Robert G. ; Meyerson, Matthew ; Hess, Jay L. / Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 3. pp. 749-754.
@article{e8d9eeb5201c488aa4d328d68559870b,
title = "Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors",
abstract = "Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.",
author = "Milne, {Thomas A.} and Hughes, {Christina M.} and Ricardo Lloyd and Zhaohai Yang and Orit Rozenblatt-Rosen and Yali Dou and Schnepp, {Robert W.} and Cynthia Krankel and LiVolsi, {Virginia A.} and Denise Gibbs and Xianxin Hua and Roeder, {Robert G.} and Matthew Meyerson and Hess, {Jay L.}",
year = "2005",
month = "1",
day = "18",
doi = "10.1073/pnas.0408836102",
language = "English (US)",
volume = "102",
pages = "749--754",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "3",

}

Milne, TA, Hughes, CM, Lloyd, R, Yang, Z, Rozenblatt-Rosen, O, Dou, Y, Schnepp, RW, Krankel, C, LiVolsi, VA, Gibbs, D, Hua, X, Roeder, RG, Meyerson, M & Hess, JL 2005, 'Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors', Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 3, pp. 749-754. https://doi.org/10.1073/pnas.0408836102

Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. / Milne, Thomas A.; Hughes, Christina M.; Lloyd, Ricardo; Yang, Zhaohai; Rozenblatt-Rosen, Orit; Dou, Yali; Schnepp, Robert W.; Krankel, Cynthia; LiVolsi, Virginia A.; Gibbs, Denise; Hua, Xianxin; Roeder, Robert G.; Meyerson, Matthew; Hess, Jay L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 3, 18.01.2005, p. 749-754.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors

AU - Milne, Thomas A.

AU - Hughes, Christina M.

AU - Lloyd, Ricardo

AU - Yang, Zhaohai

AU - Rozenblatt-Rosen, Orit

AU - Dou, Yali

AU - Schnepp, Robert W.

AU - Krankel, Cynthia

AU - LiVolsi, Virginia A.

AU - Gibbs, Denise

AU - Hua, Xianxin

AU - Roeder, Robert G.

AU - Meyerson, Matthew

AU - Hess, Jay L.

PY - 2005/1/18

Y1 - 2005/1/18

N2 - Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.

AB - Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.

UR - http://www.scopus.com/inward/record.url?scp=20044380143&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20044380143&partnerID=8YFLogxK

U2 - 10.1073/pnas.0408836102

DO - 10.1073/pnas.0408836102

M3 - Article

VL - 102

SP - 749

EP - 754

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 3

ER -