INVESTIGADORES
GALIGNIANA Mario Daniel
congresos y reuniones científicas
Título:
PKA DEPENDENT MITOCHONDRIAL -NUCLEAR REDISTRIBUTION OF FKBP51 IS REQUIRED FOR THE CONTROL OF GENE EXPRESSION DURING THE PROCESS OF ADIPOGENESIS
Autor/es:
TONEATTO J, GALIGNIANA MD, PIWIEN-PILIPUK G
Lugar:
Halle-Saale
Reunión:
Congreso; International Symposium on Cyclophilins and other Foldases: Cell Signaling Catalysts & Drug Targets; 2013
Resumen:
Obesity, one of the most prevalent health problems worldwide,
is the resultant of hypertrophy and hyperplasia of the adipose tissue accompanied
by deregulated secretion of adipokines. This makes obesity a major risk factor
for chronic diseases such as type II diabetes, cardiovascular disease, and even
cancer. Glucocorticoids regulate adipogenesis as well as distribution of
adipose tissue; therefore it is relevant to study their action at the molecular
level. They act via the
glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90?Hsp70 and
one high molecular weight immunophilin FKBP51 or FKBP52. When 3T3-L1 preadipocytes
differentiate, FKBP51 expression progressively increases, FKBP52 decreases, and
Hsp90, Hsp70, and Cyp40 remain unchanged. Interestingly, FKBP51 rapidly
translocates from mitochondria to the nucleus where it is retained upon its
interaction with chromatin and the nucleoskeleton. FKBP51 nuclear localization
is transient, after 48 h it cycles back to mitochondria. Importantly, this
dynamic FKBP51 mitochondrial-nuclear shuttling depends on PKA signaling, since
its inhibition by PKI or knock-down of PKA-cá by siRNA, abrogated FKBP51 nuclear translocation. Further, FKBP51
electrophoretic pattern of migration is altered when PKA-cá is knock-down suggesting that FKBP51 is a PKA
substrate. In preadipocytes, FKBP51 co-localizes with PKA-cá in mitochondria. When adipogenesis is triggered,
PKA-cá also moves to the nucleus co-localizing with FKBP51
mainly in the nuclear lamina, coinciding with the reorganization of this
nuclear compartment. Moreover, FKBP51 and GR interaction increases when
preadipocytes are induced to differentiate. GR transcriptional capacity is
reduced when cells are incubated in the presence of IBMX, forskolin or
dibutiryl-cAMP, compounds that induced FKBP51 nuclear translocation, but not by
a specific activator of EPAC. FKBP51 knock-down facilitates while FKBP51 ectopic
expression blocks adipogenesis. In summary, the dynamic mitochondrial-nuclear
shuttling of FKBP51 regulated by PKA may be key in the reorganization of the
nuclear lamina and the control of GR-dependent gene expression required for the
acquisition of the adipocyte phenotype.