• cancer

In Drosophila, Dmel\p53 is required for the programmed necrosis that occurs in mitotic germ cells during spermatogenesis. This form of necrosis, a non-apoptotic mechanism used to control germ cell number, involves an atypical function of the initiator caspase Dmel\Dronc, independent of its catalytic activity. Prevention of p53-dependent necrosis, by loss-of-function mutation in either p53 or Dronc, results in testicular hyperplasia. Dmel\p53 is orthologous to human TP53; Dmel\Dronc is orthologous to several caspases in human. This programmed necrosis function is conserved in vertebrate spermatogenesis, thus raising the possibility of targeting an alternative pathway in cancers that are refractory to apoptosis.

Several other genes have been tested in this system: loss-of-function mutations in Dmel\Debcl, Dmel\Pink1, or Dmel\EndoG also result in testicular hyperplasia.

The TP53 (p53) gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. The protective function of TP53 as a tumor suppressor is lost in more than 50% of human cancers.

Multiple different UAS constructs of the human gene Hsap\TP53 have been introduced into flies; heterologous rescue has not been tested. See the human disease model report 'cancer, multiple, TP53-related' (FBhh0000340). Amorphic mutations in the fly p53 gene are viable, but show abnormal stress responses, including to conditions that typically induce apoptosis (reduced levels of apoptosis observed).

A UAS construct of the wild-type human Hsap\CASP1 gene has been introduced into flies and has been used to characterize programmed cell death. Dronc is also orthologous to human CASP2 and CASP14, neither of which has been introduced into flies.

Dmel\Dronc is an initiator caspase that is essential for caspase-dependent cell death. Classical amorphic and hypomorphic mutations, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dronc. Animals homozygous for loss-of-function mutations of Dronc fail to develop beyond the larval stage; they exhibit phenotypes consistent with a failure of normal cell death in multiple tissues. Many genetic and physical interactions have been described for this gene; see below and in the Dronc gene report.

[updated Jun. 2019 by FlyBase; FBrf0222196]