Androgen-regulated formation and degradation of gap junctions in androgen-responsive human prostate cancer cells.
The constituent proteins of gap junctions, called connexins (Cxs), have a short half-life. Despite this, the physiological stimuli that control the assembly of Cxs into gap junctions and their degradation have remained poorly understood. We show here that in androgen-responsive human prostate cancer cells, androgens control the expression level of Cx32-and hence the extent of gap junction formation-post-translationally. In the absence of androgens, a major fraction of Cx32 is degraded presumably by endoplasmic reticulum-associated degradation, whereas in their presence, this fraction is rescued from degradation. We also show that Cx32 and Cx43 degrade by a similar mechanism. Thus, androgens regulate the formation and degradation of gap junctions by rerouting the pool of Cxs, which normally would have been degraded from the early secretory compartment, to the cell surface, and enhancing assembly into gap junctions. Androgens had no significant effect on the formation and degradation of adherens and tight junction-associated proteins. The findings that in a cell culture model that mimics the progression of human prostate cancer, degradation of Cxs, as well as formation of gap junctions, are androgen-dependent strongly implicate an important role of junctional communication in the prostate morphogenesis and oncogenesis.
Mitra
Shalini
S
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Annamalai
Lakshmanan
L
Chakraborty
Souvik
S
Johnson
Kristen
K
Song
Xiao-Hong
XH
Batra
Surinder K
SK
Mehta
Parmender P
PP
D000728:Androgens / Q000172:deficiency / Q000494:pharmacology*; D000818:Animals; D002450:Cell Communication; D017630:Connexins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D012190:Retroviridae; D019108:Tight Junctions / Q000378:metabolism; D000097002:Gap Junction beta-1 Protein
D000728:Androgens; D017630:Connexins; D046988:Proteasome Endopeptidase Complex; D011944:Receptors, Androgen; D000097002:Gap Junction beta-1 Protein