Testing hypotheses for the functions of APC family proteins using null and truncation alleles in Drosophila
2006
Adenomatous polyposis coli ( APC ) is mutated in colon
cancers. During normal development, APC proteins are essential negative
regulators of Wnt signaling and have cytoskeletal functions. Many functions
have been proposed for APC proteins, but these have often rested on
dominant-negative or partial loss-of-function approaches. Thus, despite
intense interest in APC, significant questions remain about its full range of
cellular functions and about how mutations in the gene affect these. We
isolated six new alleles of Drosophila APC2 . Two resemble the
truncation alleles found in human tumors and one is a protein null. We
generated ovaries and embryos null for both APC2 and APC1 ,
and assessed the consequences of total loss of APC function, allowing us to
test several previous hypotheses. Surprisingly, although complete loss of APC1
and APC2 resulted in strong activation of Wingless signaling, it did not
substantially alter cell viability, cadherin-based adhesion, spindle
morphology, orientation or selection of division plane, as predicted from
previous studies. We also tested the hypothesis that truncated APC proteins
found in tumors are dominant negative. Two mutant proteins have dominant
effects on cytoskeletal regulation, affecting Wnt-independent nuclear
retention in syncytial embryos. However, they do not have dominant-negative
effects on Wnt signaling.
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