Gli genes in development and cancer

Abstract

With the realization that many proto-oncogenes and tumor suppressor genes are expressed and have important functions during mammalian development, it is clear that cancer often involves the inappropriate activation of genetic pathways used during normal development. A signaling cascade that has been of considerable interest to both developmental and cancer biologists involves the Hedgehog (Hh) family of secreted proteins. To date, the only transcription factors shown to be directly downstream of Hh are the zinc-finger containing proteins Cubitus interruptus (Ci) and Gli, in flies and vertebrates, respectively. The identification of many of the genes and proteins involved in Hh signaling has come largely from genetic and biochemical studies in Drosophila. Ci mediates Hh signaling through a Hh-dependent set of protein modifications that alter the activity of Ci on Hh target genes. Recent evidence suggests vertebrate Gli proteins may be similarly regulated. The interest in this pathway has taken on added importance with the identification of mutations in Hh pathway genes, including Gli genes, in several human developmental disorders and cancers. We discuss models for how Gli proteins mediate Hh signaling in both vertebrate development and cancers.

Enhanced expression of hedgehog signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions

“…However, Gli-2 and Gli-3 could function either as oncogenes or tumor suppressors, depending on the type of mutation and cellular context. 6 However, Gli-2 is known to have a redundant function with Gli-1 and has been implicated in tumorigenesis. 2 According to our results, Gli-2 may play a more important role than Gli-1.…”

“…On the other hand, Gli-2 and Gli-3 function as oncogenes or tumor suppressors, depending on the type of mutation and cellular context. 6 The deregulation of Hh-signaling pathway has been implicated in several types of cancers. [2][3][4] The mutational activation of the Hh-signaling pathway, whether sporadic or in Gorlin's syndrome, is associated with tumorigenesis in a small subset of these tissues, predominantly skin, the cerebellum, and skeletal muscle.…”

Hedgehog Signaling Regulates Sebaceous Gland Development

“…30,31 Gli proteins mediate transcriptional responses to Hedgehog family members, 19,20 and the Gli2⌬C4 transactivation-domain mutant blocks Gli func-tion in a dominant-negative manner. 22 To inhibit Hedgehog signaling selectively in cutaneous epithelium, we used the bovine K5 promoter 23 to generate K5-Gli2⌬C4 transgenic mice.…”

Xmeis1, a protooncogene involved in specifying neural crest cell fate in Xenopus embryos

“…We ®nd that overexpression of Xmeis1 in ectodermal explants induces XGli-3 and XZic3 expression, while XGli-1 is not a ected (Figure 4). Gli and Zic genes, like Xmeis1b, induce neural tissue in animal cap explants (Nakata et al, 1997;Ruizi Altaba, 1998;Brewster et al, 1998;Matise et al, 1998;Ding et al, 1998) and it is interesting that Xmeis1b induces XGli-3 which is normally expressed in dorsal neural tube from where neural crest emanates (Marine et al, 1997), but does not induce XGli-1 which is found ventrally within the neural tube. Moreover, transverse sections revealed that Xmeis1b induced an accumulation of ectopic pigmented cells in the embryo, and pigmented cells are often derived from neural crest.…”