Intra-allelic suppression of a mutation that stabilizes microtubules and confers resistance to colcemid

Biochemistry
Yaqing WangFernando Cabral

Abstract

Cmd 4 is a colcemid resistant beta-tubulin mutant of Chinese hamster ovary cells that exhibits hypersensitivity to paclitaxel and temperature sensitivity for growth. The mutant beta-tubulin allele in this cell line encodes a D45Y amino acid substitution that produces colcemid resistance by making microtubules more stable. By selecting revertants of the temperature sensitive and paclitaxel hypersensitive phenotypes, we have identified three cis-acting suppressors of D45Y. One suppressor, V60A, maps to the same region as the D45Y alteration, and a second suppressor, Q292H, maps to a distant location. Both appear to produce compensatory changes in microtubule assembly that counteract the effects of the original D45Y substitution. Consistent with this view, expression of the V60A mutation in transfected wild-type cells produced paclitaxel resistance and greatly decreased microtubule assembly. Additionally, it produced a paclitaxel-dependent phenotype in which cells grew normally in the presence, but not the absence, of the drug. The Q292H mutation caused even greater disassembly of microtubules such that cells were unable to proliferate when the transgene was expressed; but, unlike the V60A mutation, cell growth could not be rescue...Continue Reading

References

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Citations

Mar 24, 2006·The Journal of Biological Chemistry·Yaqing WangFernando Cabral
Jan 28, 2010·Molecular Cancer Therapeutics·Shanghua YinFernando Cabral
Jul 12, 2011·Biochimica Et Biophysica Acta·Anutosh Ganguly, Fernando Cabral
Jun 14, 2005·Biochimica Et Biophysica Acta·Yaqing Wang, Fernando Cabral
Mar 18, 2008·American Journal of Physiology. Heart and Circulatory Physiology·Guangmao ChengGeorge Cooper
Jul 14, 2007·The Journal of Biological Chemistry·Hailing Yang, Fernando Cabral
Jun 16, 2005·Molecular Cancer Therapeutics·Chia-Ping Huang YangSusan Band Horwitz
Mar 11, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Tuyelee DasAbhijit Dey

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