Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 28, Pages 9766-9771Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0503891102
Keywords
3T3-L1 preadipocyte; cell cycle; differentiation; mitotic clonal expansion
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Funding
- NIDDK NIH HHS [DK 38418, K01 DK061355, R01 DK038418, K01 DK 61355] Funding Source: Medline
- PHS HHS [K 61840] Funding Source: Medline
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CCAAT enhancer-binding protein (C/EBP)beta, C/EBP alpha, and peroxisome proliferator activated receptor (PPAR)gamma act in a cascade where C/EBP beta activates expression of C/EBP alpha and PPAR gamma, which then function as pleiotropic activators of genes that produce the adipocyte phenotype. When growth-arrested 3T3-L1 preadipocytes are induced to differentiate, C/EBP beta is rapidly expressed but still lacks DNA-binding activity. After a long (14-hour) lag, glycogen synthase kinase 313 enters the nucleus, which correlates with hyperphosphorylation of C/EBP beta and acquisition of DNA-binding activity. Concurrently, 3T3-L1 preadipocytes synchronously enter S phase and undergo mitotic clonal expansion, a prerequisite for terminal differentiation. Ex vivo and in vitro experiments with C/EBP beta show that phosphorylation of Thr-188 by mitogen-activating protein kinase primes C/EBP beta for subsequent phosphorylation on Ser-184 and Thr-179 by glycogen synthase kinase 30, acquisition of DNA-binding function, and transactivation of the C/EBP alpha and PPAR gamma genes. The delayed transactivation of the C/EBP alpha and PPAR gamma genes by C/EBP beta appears necessary to allow mitotic clonal expansion, which would otherwise be prevented, because C/EBP alpha and PPAR-gamma are antimitotic.
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