Molecule-phenotype association

Knockout of the prolactin receptor, rather than knockout of prolactin, is necessary to explore the role of the hormone and its receptor in maternal behavior because several molecules other than prolactin, including growth hormone (GH) and placental lactogens, may stimulate the prolactin receptor. Disruption of the prolactin receptor gene in a mouse model has allowed for assessment of phenotypes associated with partial and complete prolactin receptor deficits (Goffin et ah, 1999). Prolactin receptor knockout mice have severe reproductive deficits. Heterozygous mothers (receptor —/+) were also unable to lactate (Bridges, 1998). 

Fouchier, R. A., Groenink, M., Kootstra, N. A., Tersmette, M., Huisman, H. G., et al. (1992) Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gpl20 molecule. J. Virol. 66, 3183-3187. 

The activity of either isoenzyme, naturally, depends, to a great degree, upon which variant of a given multienzyme system will be realized. Since in some cases some of the enzyme molecules cannot associate, this could occur, for instance, as a result of a lack of conformational accordance. Thus, the complex effect of differences in translation rate and also post-translational events (assembly with membranes or inhibitors, degradation, formation of multienzyme complexes, etc.) is an important factor in the realization of differential expression of biochemical traits in the phenotype. 

We observed that reproducibility of small-molecule phenotypes was increased if the lymphoblast cells were maintained (through counting and dilution daily) at a concentration associated with exponential growth for at least 2 weeks from the initial thaw to harvest for screening [11]. Note that LCLs grow as nonadherent clumps. 

Unlike the situation with the integrins discussed earlier, it is loss of cadherin E that promotes metastasis. The evidence linking loss or decreased expression of cadherin E with cancer spread is as follows (M2). Firstly, a negative correlation exists between the expression of cadherin E and invasion for many different cancer cell lines. Secondly, in cell lines lacking cadherin E, invasion could be prevented by transfection with cDNA for this cadherin. Thirdly, reduction in cadherin E mRNA levels by antisense sequences induced the invasive phenotype in E-cadherin positive cells. Fourthly, antibodies inactivating cadherin E induced the invasive phenotype. These combined experiments are strong evidence that loss of cadherin E is associated with development of invasive phenotype and furthermore suggests that this adhesion molecule may be a suppressor of metastasis. 

There is much more to this functional complexity than we have been able to discuss in this review. For instance, we have not touched on the complex intranuclear network mediated by the nuclear lamins, which is critically important for human health as reflected in the numerous disease phenotypes that are emerging due to mutation in lamins and their associated protein partners. We have also not discussed the association of IFs with molecules involved in bacterial and viral pathogenesis, such as the Ebstein-Barr virus latent infection membrane protein (LMP) (Liebowitz et al., 1987) or viral kinases such as the herpes simplex virus US3 kinase (Murata et at, 2002) that may be important in remodeling IFs during infection. It is clear, however, from the many critical cellular functions we have discussed in this review, that the IF structural and signaling scaffold is involved in wide-ranging functions that are important for fundamental... 

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