Refining the Role of Lgl, Dlg and Scrib in Tumor Suppression and Beyond: Learning from the Old Time Classics
Abstract
Cancer was first described as an unrestricted proliferation of cells leading to a complex pattern of defects, which ultimately result in the death of the host. A genetic mechanism identified in the 1960-70s, first in Drosophila and then in human, involves recessive mutations occurring in specific developmental genes.
The molecular identification of the lgl, dlg and scribble tumour suppressor genes in Drosophila shows that their products consist of cytoskeletal associated-proteins acting primarily in cell polarity and cell architecture. If this structural function could be sufficient to explain some of the aspects of neoplastic proliferation, such as alterations in signal transduction between cells, other defects remain however unexplained.
Investigations performed on apparently normal cells, albeit homozygous mutated, show for example that the lgl salivary glands can respond to the hormone ecdysone by producing primary response products but the subsequent genetic response is blocked as these products are unable to gain access to chromatin. Access to chromatin of transcriptional regulators and chromatin modifying enzymes requires a cytoplasmic interaction between Lgl and non-muscle myosin II heavy chain.
In the absence of Lgl the genetic cascade is blocked resulting in a genomic frost and inability of the lgl tissue to dye. This review describes the current knowledge of the function of these genes in Drosophila and the possible function of their homologs in higher vertebrates.