Ct. Taylor et al., Phosphorylation-dependent targeting of cAMP response element binding protein to the ubiquitin/proteasome pathway in hypoxia, P NAS US, 97(22), 2000, pp. 12091-12096
Citations number
38
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Hypoxia activates a number of gene products through degradation of the tran
scriptional coactivator cAMP response element binding protein (CREB). Other
transcriptional regulators (e.g., beta -catenin and NF-kappaB) are control
led through phosphorylation-targeted proteasomal degradation, and thus, we
hypothesized a similar degradative pathway for CREB. Differential display a
nalysis of mRNA derived from hypoxic epithelia revealed a specific and time
-dependent repression of protein phosphatase 1 (PP1), a serine phosphatase
important in CREB dephosphorylation. Subsequent studies identified a previo
usly unappreciated proteasomal-targeting motif within the primary structure
of CREB (DSVTDS), which functions as a substrate for PP1. Ambient hypoxia
resulted in temporally sequential CREB serine phosphorylation, ubiquitinati
on, and degradation tin vitro and in vivo). HIV-tat peptide-facilitated loa
ding of intact epithelia with phosphopeptides corresponding to this proteas
ome targeting motif resulted in inhibition of CREB ubiquitination. Further
studies revealed that PP1 inhibitors mimicked hypoxia-induced gene expressi
on, whereas proteasome inhibitors reversed the hypoxic phenotype. Thus, hyp
oxia establishes conditions that target CREB to proteasomal degradation. Th
ese studies may provide unique insight into a general mechanism of transcri
ptional regulation by hypoxia.