Ken & Barbie Selectively Regulates the Expression of a Subset of JAK/STAT Pathway Target Genes

Abstract

A limited number of evolutionarily conserved signal transduction pathways are repeatedly reused during development to regulate a wide range of processes. Here we describe a new negative regulator of JAK/STAT signaling and identify a potential mechanism by which the pleiotropy of responses resulting from pathway activation is generated in vivo. As part of a genetic interaction screen, we have identified Ken & Barbie (Ken) , which is an ortholog of the mammalian proto-oncogene BCL6 , as a negative regulator of the JAK/STAT pathway. Ken genetically interacts with the pathway in vivo and recognizes a DNA consensus sequence overlapping that of STAT92E in vitro. Tissue culture-based assays demonstrate the existence of Ken-sensitive and Ken-insensitive STAT92E binding sites, while ectopically expressed Ken is sufficient to downregulate a subset of JAK/STAT pathway target genes in vivo. Finally, we show that endogenous Ken specifically represses JAK/STAT-dependent expression of ventral veins lacking (vvl) in the posterior spiracles. Ken therefore represents a novel regulator of JAK/STAT signaling whose dynamic spatial and temporal expression is capable of selectively modulating the transcriptional repertoire elicited by activated STAT92E in vivo.

JAK/STAT signalling inDrosophila: insights into conserved regulatory and cellular functions

“…A role for Ken & Barbie (KEN) in the selective regulation of STAT92E activity has also recently been demonstrated, a finding that could advance our understanding of how a single pathway can mediate diverse developmental processes (Arbouzova et al, 2006). KEN is the Drosophila homologue of human BCL6 (B-cell lymphoma 6) and belongs to the family of BTB/POZ domaincontaining transcriptional repressors (Fig.…”

Unphosphorylated STATs go nuclear

“…Specifically, those STAT92E-binding sites containing a GAAA (i.e. an additional A in their final position) are recognised and repressed by Ken, so down-regulating a specific subset of pathway target genes at multiple stages of development [13]. More recently, Kwon et al have revealed a potential mechanism for Ken-mediated transcriptional repression [14 ].…”

“…by inappropriate JAK/STAT pathway activation. The first of these, using ectopic Upd expression in the eye as its assay identified a number of genes, including the histone variant, His2A.V and the ken and barbie (ken) locus [12,13] ( Table 1). ken encodes a site-specific transcriptional repressor that binds to a DNA site made up of an essential core sequence present within the palindromic nTTCnnnGAAn sites recognised by STAT92E.…”

Specific Localization of the Drosophila Telomere Transposon Proteins and RNAs, Give Insight in Their Behavior, Control and Telomere Biology in This Organism

“…STAT then activates a downstream pathway. Ken, a DNA binding protein is among the different downstream targets of the JAK-STAT pathway [45]. Interestingly, we have recently demonstrated that Ken is involved in the control of Drosophila telomeres by regulating the expression of the TART retrotransposon through specific binding sites [17].…”