Many hormones repress or enhance protein expression by binding to
transcription factors called nuclear receptors. Other hormones regulate
processes by binding to cell surface receptors that induce cell signaling
cascades.
A. Represent these two different processes for cell-cell communication by
creating a flow chart showing the direction of information in a process
regulating
homeostasis such as the control of blood sugar or water loss. Annotate your
diagram to describe the key elements of each step in the particular example
that you choose.
B. Justify the claim that a developmental process is more likely to involve
nuclear receptors, while regulation of metabolism is more likely to involve
cell surface receptors. The lancelet is a chordate, fish-like filter feeder
that buries itself in marine sands. Their ancestors and vertebrates
diverged approximately 500 million years ago. Lancelet and human are members
of a superphylum of animals with bilateral symmetry, Deuterostomia. In one
model of animal evolution, the other superphylum, Protostomia, includes fruit
fly and nematode. In an alternative model, insects are included with lancelet
and human in a superphylum called the Coelomata, and the nematode is separate.
Molecular studies of fruit fly, lancelet, human, and nematode show that
homologous genes, when present, are strongly conserved. For example, the genes
for the receptors of germ cell nuclear factor (GCNF) and retinoids, hormones
that regulate cellular differentiation during development, are present in each
species. Homologous genes for nuclear receptor estrogen and thyroid hormone
are present in lancelet and human but missing in nematode and fruit fly. Genes
for the vitamin D
receptor are absent in fruit fly but are present in the other species. Many
neuropeptide hormones found in human, fruit fly and nematode such as GnRH
(gonadotropin-releasing hormone) and the gonadotropins luteinizing and
follicle stimulating hormones (LH and FSH) have not been found in lancelet.
However, genes for the cell surface receptors activated by these hormones are
expressed. The same is true for many different hormones and their
corresponding receptors. A large number of such 鈥渙rphan鈥� nuclear receptors
have been reported in animals where there is no
evidence of the presence of the hormone to which they bind.
C. Analyze these data (a table to organize the data is suggested) for
supporting evidence of the alternative superphylum, Coelomata. Consider:
鈥� separate selection of signaling molecules and the
proteins that detect them
鈥� constitutive (always transcribed) expression
鈥� the possible effect of gene deletion
D. Evaluate the legitimacy of a claim that a hormone is not present although
the receptor for that hormone has been found. Genes for receptors and the
hormones to which they bind
are often found on different chromosomes and have coevolved. Other ligands may
have an affinity for orphaned receptors. By understanding the three-
dimensional shape of the ligand binding site of a nuclear receptor, new drugs
can be developed to match the site and regulate expression when the endocrine
system fails. Even greater flexibility in drug design is allowed when small
molecules, called positive (PAM) and negative (NAM) allosteric modulators,
change the shape of the ligand binding site. The receptors for follicle
stimulating hormone (FSH) and luteinizing hormone (LH) were subjects in a drug
discovery program using PAMs and NAMs (Nataraja et al., Frontiers in
Endocrinology, 6, 2015).
E. Explain how the refinement of nuclear receptor by attachment of a molecule
other than the ligand of the receptor can increase the level of expression of
genes targeted by the transcription factor
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