Biomedical subjects

G Armin

Publications and source records attributed to G Armin.

2 recordsLinked to original sources

PubMed1998

Altered expression of ubiquitous kinesin heavy chain results in resistance to etoposide and hypersensitivity to colchicine: mapping of the domain associated with drug response.

The motor protein kinesin is a tetramer consisting of two heavy and two light chains. Expression of an antisense RNA fragment derived from the mouse ubiquitous kinesin heavy chain (uKHC) cDNA is associated with a unique type of multidrug resistance. We analyzed the effects of retroviral transduction of the human uKHC and its derivatives on drug sensitivity of the human fibrosarcoma cell line HT1080. Surprisingly, overexpression of full-length uKHC and its variants that were deficient in the NH2-terminal motor domain produced a phenotype similar to that of antisense RNA, characterized by resistance to etoposide and collateral sensitivity to colchicine. This altered drug response, therefore, appears to be a general consequence of kinesin deregulation. The genetic suppressor element approach was applied to map the determinants of drug response in the kinesin heavy chain. A sense-oriented genetic suppressor element conferring resistance to etoposide was isolated from a retroviral library of randomly fragmented uKHC cDNA. This element encodes the last 55 amino acids of uKHC, suggesting that the COOH-terminal tail domain of uKHC is involved in the cellular drug response.

3T3 Cells↗

PubMed1997

Transgenic mice with p53-responsive lacZ: p53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo.

To analyze the involvement of p53-dependent transcriptional activation in normal development and in response to DNA damage in vivo, we created transgenic mice with a lacZ reporter gene under the control of a p53-responsive promoter. Five independent strains showed similar patterns of transgene expression. In untreated animals, lacZ expression was limited to the developing nervous system of embryos and newborn mice and was strongly decreased in the adult brain. gamma-irradiation or adriamycin treatment induced lacZ expression in the majority of cells of early embryos and in the spleen, thymus and small intestine in adult mice. Transgene expression was p53 dependent and coincided with the sites of strong p53 accumulation. The lacZ-expressing tissues and early embryos, unlike other adult tissues and late embryos, are characterized by high levels of p53 mRNA expression and respond to DNA damage by massive apoptotic cell death. Analysis of p53-null mice showed that this apoptosis is p53 dependent. These data suggest that p53 activity, monitored by the reporter lacZ transgene, is the determinant of radiation and drug sensitivity in vivo and indicate the importance of tissue and stage specificity of p53 regulation at the level of mRNA expression.

3T3 Cells↗