Cyclin D

DEVELOPMENTAL BIOLOGY

Embryonic and larval

Drosophila Cyclin D is expressed in early embryos and in imaginal disc cells in a pattern that anticipates cell divisions. Expression in the developing eye disc at the anterior edge of the morphogenetic furrow suggests that Cyclin D acts early, prior to Cyclin E, in inducing G1-arrested cells to enter S phase. The pattern of expression is similar to that of string, although string expression precedes that of Cyclin D. Anterior to the furrow, cells divide asynchronously, but at the anterior edge of the furrow, all cells arrest in G1 phase of the cell cycle. Those cells destined to divide enter S in synchrony just posterior to the furrow, while the remaining clustered post-mitotic cells begin to differentiate. Although Cyclin D may be necessary, its expression alone is not sufficient to initiate the events leading to S phase (Finley 1996).

Effects of Mutation

Mutations have been characterized in the Drosophila Tsc1 and Tsc2/gigas genes. Inactivating mutations in either gene cause an identical phenotype characterized by enhanced growth and increased cell size with no change in ploidy. Overall, mutant cells spend less time in G1. Coexpression of both Tsc1 and Tsc2 restricts tissue growth and reduces cell size and cell proliferation. This phenotype is modulated by manipulations in cyclin levels. In postmitotic mutant cells, levels of Cyclin E and Cyclin A are elevated. This correlates with a tendency for these cells to reenter the cell cycle inappropriately as is observed in the human lesions (Tapon, 2001).

The enhanced growth observed in the Tsc1 or Tsc2 mutants most resembles the results of inactivating PTEN or increasing Ras1 or dmyc activity. In each of these situations, there is a reduction in the length of the G1 phase. In contrast, increased growth driven by Cyclin D/cdk4 does not alter the distribution of cells in different phases of the cell cycle. The effects of the combined overexpression of Tsc1 and Tsc2 displays genetic interactions with multiple pathways. The phenotype is influenced by alterations in the levels of dS6K, PTEN, Ras1, dmyc, cyclin D, and cdk4. Thus, Tsc1 and Tsc2 may function downstream of the point of convergence of these pathways. Alternatively, Tsc1 and Tsc2 may primarily antagonize one of these pathways, but this effect could be overcome by increasing the activity of one of the others (Tapon, 2001).

While the increased levels of cyclins are likely to be a response to the increased growth rate of mutant cells, the possibility that they are in some way responsible for the increased growth rate cannot be excluded. In Drosophila, the Cyclin D/cdk4 complex serves to promote growth. In such a scenario, the loss of Tsc1 or Tsc2 gene function may lead to elevated levels of cyclins leading to increased growth and proliferation. Surprisingly, increased expression of Cyclin E, which is thought to primarily promote S-phase entry and not growth, is also able to suppress the phenotype induced by overexpression of Tsc1 and Tsc2. This might reflect the existence of feedback loops where Cyclin E might downregulate the levels or activity of the Tsc1/Tsc2 complex. Alternatively, in some circumstances, Cyclin E might assume some of the functions of the growth promoting Cyclin D. Indeed, in mammalian cells, cyclin E has been shown to fully compensate for the loss of cyclin D1 (Tapon, 2001).

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Cyclin D: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology 

date revised: 22 March 2022

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