Activation of peroxisome proliferator-activated receptor gamma bypasses the function of the retinoblastoma protein in adipocyte differentiation

TY - JOUR

T1 - Activation of peroxisome proliferator-activated receptor gamma bypasses the function of the retinoblastoma protein in adipocyte differentiation

AU - Hansen, Jacob B.

AU - Petersen, R K

AU - Larsen, B M

AU - Bartkova, J

AU - Alsner, J

AU - Kristiansen, K

N1 - Keywords: Adipocytes; Animals; Base Sequence; CCAAT-Enhancer-Binding Proteins; Cell Cycle; Cell Differentiation; Cells, Cultured; DNA Primers; DNA-Binding Proteins; Embryo, Mammalian; Mice; Nuclear Proteins; Receptors, Cytoplasmic and Nuclear; Retinoblastoma Protein; Transcription Factors; Transcriptional Activation

PY - 1999

Y1 - 1999

N2 - The retinoblastoma protein (pRB) is an important regulator of development, proliferation, and cellular differentiation. pRB was recently shown to play a pivotal role in adipocyte differentiation, to interact physically with adipogenic CCAAT/enhancer-binding proteins (C/EBPs), and to positively regulate transactivation by C/EBPbeta. We show that PPARgamma-mediated transactivation is pRB-independent, and that ligand-induced transactivation by PPARgamma1 present in RB+/+ and RB-/- mouse embryo fibroblasts is sufficient to bypass the differentiation block imposed by the absence of pRB. The differentiated RB-/- cells accumulate lipid and express adipocyte markers, including C/EBPalpha and PPARgamma2. Interestingly, adipose conversion of pRB-deficient cells occurs in the absence of compensatory up-regulations of the other pRB family members p107 and p130. RB+/+ as well as RB-/- cells efficiently exit from the cell cycle after completion of clonal expansion following stimulation with adipogenic inducers. We conclude that ligand-induced activation of endogenous PPARgamma1 in mouse embryo fibroblasts is sufficient to initiate a transcriptional cascade resulting in induction of PPARgamma2 and C/EBPalpha expression, withdrawal from the cell cycle, and terminal differentiation in the absence of a functional pRB.

AB - The retinoblastoma protein (pRB) is an important regulator of development, proliferation, and cellular differentiation. pRB was recently shown to play a pivotal role in adipocyte differentiation, to interact physically with adipogenic CCAAT/enhancer-binding proteins (C/EBPs), and to positively regulate transactivation by C/EBPbeta. We show that PPARgamma-mediated transactivation is pRB-independent, and that ligand-induced transactivation by PPARgamma1 present in RB+/+ and RB-/- mouse embryo fibroblasts is sufficient to bypass the differentiation block imposed by the absence of pRB. The differentiated RB-/- cells accumulate lipid and express adipocyte markers, including C/EBPalpha and PPARgamma2. Interestingly, adipose conversion of pRB-deficient cells occurs in the absence of compensatory up-regulations of the other pRB family members p107 and p130. RB+/+ as well as RB-/- cells efficiently exit from the cell cycle after completion of clonal expansion following stimulation with adipogenic inducers. We conclude that ligand-induced activation of endogenous PPARgamma1 in mouse embryo fibroblasts is sufficient to initiate a transcriptional cascade resulting in induction of PPARgamma2 and C/EBPalpha expression, withdrawal from the cell cycle, and terminal differentiation in the absence of a functional pRB.

M3 - Journal article

C2 - 9891007

SN - 0021-9258

VL - 274

SP - 2386

EP - 2393

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 4

ER -