TY - JOUR
T1 - A Novel Role for High-Mobility Group A Proteins in Cellular Senescence and Heterochromatin Formation
AU - Narita, Masashi
AU - Narita, Masako
AU - Krizhanovsky, Valery
AU - Nuñez, Sabrina
AU - Chicas, Agustin
AU - Hearn, Stephen A.
AU - Myers, Michael P.
AU - Lowe, Scott W.
N1 - Funding Information:
We thank G. Hannon, V. Giancotti, A. Levine, E. Heard, and J. Gil for reagents and members of the Lowe laboratory for stimulating discussions. This work was supported by fellowships from the Department of Defense Breast Cancer Research Program (M.N., S.N.), the Leukemia and Lymphoma Society (V.K.), and a postdoctoral fellowship (A.C.) and grant AG16379 (S.W.L.) from the National Institutes of Health. S.W.L. is a Howard Hughes Medical Institute investigator.
PY - 2006/8/4
Y1 - 2006/8/4
N2 - Cellular senescence is a stable state of proliferative arrest that provides a barrier to malignant transformation and contributes to the antitumor activity of certain chemotherapies. Senescent cells can accumulate senescence-associated heterochromatic foci (SAHFs), which may provide a chromatin buffer that prevents activation of proliferation-associated genes by mitogenic transcription factors. Surprisingly, we show that the High-Mobility Group A (HMGA) proteins, which can promote tumorigenesis, accumulate on the chromatin of senescent fibroblasts and are essential structural components of SAHFs. HMGA proteins cooperate with the p16INK4a tumor suppressor to promote SAHF formation and proliferative arrest and stabilize senescence by contributing to the repression of proliferation-associated genes. These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers. Our results identify a component of the senescence machinery that contributes to heterochromatin formation and imply that HMGA proteins also act in tumor suppressor networks.
AB - Cellular senescence is a stable state of proliferative arrest that provides a barrier to malignant transformation and contributes to the antitumor activity of certain chemotherapies. Senescent cells can accumulate senescence-associated heterochromatic foci (SAHFs), which may provide a chromatin buffer that prevents activation of proliferation-associated genes by mitogenic transcription factors. Surprisingly, we show that the High-Mobility Group A (HMGA) proteins, which can promote tumorigenesis, accumulate on the chromatin of senescent fibroblasts and are essential structural components of SAHFs. HMGA proteins cooperate with the p16INK4a tumor suppressor to promote SAHF formation and proliferative arrest and stabilize senescence by contributing to the repression of proliferation-associated genes. These antiproliferative activities are canceled by coexpression of the HDM2 and CDK4 oncogenes, which are often coamplified with HMGA2 in human cancers. Our results identify a component of the senescence machinery that contributes to heterochromatin formation and imply that HMGA proteins also act in tumor suppressor networks.
UR - http://www.scopus.com/inward/record.url?scp=33746752125&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2006.05.052
DO - 10.1016/j.cell.2006.05.052
M3 - Article
C2 - 16901784
AN - SCOPUS:33746752125
SN - 0092-8674
VL - 126
SP - 503
EP - 514
JO - Cell
JF - Cell
IS - 3
ER -