Disease relevance of dm

• The dMyc protein is likely encoded by the Drosophila gene diminutive (dm), a mutation in which results in small body size and female sterility caused by degeneration of the ovaries [1].
• Premature expression of Myc-Don Juan Like does not impair spermatogenesis where-as Don Juan-eGFP when prematurely expressed causes male sterility as spermatids fail to individualize [2].

High impact information on dm

• While Prospero regulates cell-cycle gene transcription, Brat acts as a posttranscriptional inhibitor of dMyc [3].
• This homeostatic mechanism coordinates rates of G1-->S and G2-->M progression, maintaining normal rates of proliferation when cell cycle controls are perturbed (e.g., by ectopic Dacapo, dWee1, dMyc, or Rheb) [4].
• Here we use Drosophila imaginal discs to mimic situations in which cells with unequal levels of Myc protein are apposed and show that this invariably elicits a win/lose situation reminiscent of cell competition; cells with lower levels of dMyc are eliminated by apoptosis whereas cells with higher levels of dMyc over-proliferate [5].
• Ras upregulated the growth driver dMyc, and both Ras and dMyc increased levels of cyclin E posttranscriptionally [6].
• Our results indicate that dMyc links patterning signals to cell division by regulating primary targets involved in cellular growth and metabolism [7].

Biological context of dm

• We have used dm(4), a new null allele of the Drosophila diminutive (dm) gene, which encodes dMyc on the X chromosome, to investigate a role for dMyc in larval endoreplicating tissues, where cellular growth and DNA replication occur in the absence of cell division [8].
• Myc acts through dimerization with Max to bind DNA and activate transcription [1].
• Homologs of the myc and max genes were cloned from the fruit fly Drosophila melanogaster and their protein products (dMyc and dMax) were shown to heterodimerize, recognize the same DNA sequence as their vertebrate homologs, and activate transcription [1].
• The transcription factor dMyc is the sole Drosophila ortholog of the vertebrate c-myc protooncogenes and a central regulator of growth and cell-cycle progression during normal development [9].
• Members of the Myc family of proto-oncogenes have long been implicated in regulating proliferation, apoptosis and oncogenesis [8].

Anatomical context of dm

• These findings indicate a potential role for Myc in germ cell development and set the stage for genetic analysis of Myc and Max [1].
• However, in cases in which the entire germline cyst or the whole follicular epithelium was mutant for dm, the growth of the entire follicle, including the wild-type cells, was delayed [10].
• Surprisingly, despite their impaired ability to endoreplicate, dm mutant follicle cells appeared to carry out chorion gene amplification normally [10].
• We suggest that during animal development, the control of rRNA synthesis and ribosome biogenesis is an essential Myc function [11].
• Microinjection into oocytes of in vitro transcribed mRNA prepared from a Myc-tagged construct of the somatic topoisomerase I sequence is translated to yield a 110 kDa product [12].

Physical interactions of dm

• Structural conservation in regions of known functional significance is consistent with the ability of dMyc1 to interact with vertebrate Max, to transactivate gene expression in yeast cells, and to cooperate with activated H-RAS to effect the malignant transformation of primary mammalian cells [13].
• Our results suggest that the dMyc-Groucho complex defines a previously undescribed mechanism of Myc function and may serve as the transcriptional unit that integrates EGF and Notch inputs to regulate early neuronal development [14].

Regulatory relationships of dm

• Mechanistically, InR/Foxo signaling controls cell cycle progression by modulating dmyc expression and dMyc transcriptional activity [15].

Other interactions of dm

• In support of this, dMyc, as well as its antagonist dMnt, are expressed in larval tissues in a pattern consistent with their involvement in regulating endoreplication [8].
• We also demonstrate that the pattern of dMyc expression in nuclei overlaps with histone markers of active chromatin but not pericentric heterochromatin. dMyc binding is not detected on the X chromosome rDNA cluster (bobbed locus) [16].
• Our findings indicate that Hfp provides a critical molecular link between the developmental patterning signals induced by the wingless pathway and dMyc-regulated cell growth and proliferation [17].
• Recent experiments suggest the existence of a transcriptional network that functions in parallel to the canonical Myc/Max/Mad transcriptional network [18].

Analytical, diagnostic and therapeutic context of dm

• Chromatin immunoprecipitation confirmed that many dMyc-Pc-repressed loci have an epigenetic mark recognized by Pc [19].

References