In the
biological
Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary in ...
context of
organisms'
production
Production may refer to:
Economics and business
* Production (economics)
* Production, the act of manufacturing goods
* Production, in the outline of industrial organization, the act of making products (goods and services)
* Production as a stat ...
of
gene products
A gene product is the biochemical material, either RNA or protein, resulting from expression of a gene. A measurement of the amount of gene product is sometimes used to infer how active a gene is. Abnormal amounts of gene product can be correlate ...
, downregulation is the process by which a
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
decreases the quantity of a cellular component, such as
RNA or
protein, in response to an external stimulus. The complementary process that involves increases of such components is called upregulation.
An example of downregulation is the cellular decrease in the expression of a specific
receptor
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
in response to its increased activation by a molecule, such as a
hormone or
neurotransmitter, which reduces the cell's sensitivity to the molecule. This is an example of a locally acting (
negative feedback
Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...
) mechanism.
An example of upregulation is the response of
liver cells exposed to such
xenobiotic molecules as
dioxin. In this situation, the cells increase their production of
cytochrome P450 enzymes, which in turn increases degradation of these dioxin molecules.
Downregulation or upregulation of an RNA or protein may also arise by an
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
alteration. Such an epigenetic alteration can cause expression of the RNA or protein to no longer respond to an external stimulus. This occurs, for instance, during
drug addiction or
progression to cancer.
Downregulation and upregulation of receptors
All living cells have the ability to receive and process signals that originate outside their membranes, which they do by means of proteins called
receptors
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
, often located at the cell's surface imbedded in the plasma membrane. When such signals interact with a receptor, they effectively direct the cell to do something, such as dividing, dying, or allowing substances to be created, or to enter or exit the cell. A cell's ability to respond to a chemical message depends on the presence of receptors tuned to that message. The more receptors a cell has that are tuned to the message, the more the cell will respond to it.
Receptors are created, or expressed, from instructions in the DNA of the cell, and they can be increased, or upregulated, when the signal is weak, or decreased, or downregulated, when it is strong. Their level can also be up or down regulated by modulation of systems that degrade receptors when they are no longer required by the cell.
Downregulation of receptors can also occur when receptors have been chronically exposed to an excessive amount of a ligand, either from
endogenous mediators or from
exogenous
In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It contrasts with endogeneity or endogeny, the fact of being influenced within a system.
Economics
In an economic model, an exogen ...
drugs. This results in
ligand-induced desensitization or internalization of that receptor. This is typically seen in animal hormone receptors. Upregulation of receptors, on the other hand, can result in super-sensitized cells especially after repeated exposure to an antagonistic drug or prolonged absence of the ligand.
Some
receptor agonists may cause downregulation of their respective receptors, while most
receptor antagonists temporarily upregulate their respective receptors. The disequilibrium caused by these changes often causes
withdrawal when the long-term use of a
drug is discontinued.
Upregulation and downregulation can also happen as a response to
toxins or
hormones. An example of upregulation in
pregnancy is hormones that cause cells in the
uterus to become more sensitive to
oxytocin
Oxytocin (Oxt or OT) is a peptide hormone and neuropeptide normally produced in the hypothalamus and released by the posterior pituitary. It plays a role in social bonding, reproduction, childbirth, and the period after childbirth. Oxytocin ...
.
Example: Insulin receptor downregulation
Elevated levels of the hormone
insulin in the blood trigger downregulation of the associated receptors. When insulin binds to its receptors on the surface of a cell, the hormone receptor complex undergoes
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
and is subsequently attacked by intracellular
lysosomal
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pro ...
enzymes
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...
. The internalization of the insulin molecules provides a pathway for degradation of the hormone as well as for regulation of the number of sites that are available for binding on the cell surface. At high plasma concentrations, the number of surface receptors for insulin is gradually reduced by the accelerated rate of receptor internalization and degradation brought about by increased hormonal binding.
The rate of
synthesis
Synthesis or synthesize may refer to:
Science Chemistry and biochemistry
* Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors
**Organic synthesis, the chemical synthesis of organ ...
of new receptors within the
endoplasmic reticulum and their insertion in the plasma membrane do not keep pace with their rate of destruction. Over time, this self-induced loss of target cell receptors for insulin reduces the target cell's sensitivity to the elevated hormone concentration.
This process is illustrated by the
insulin receptor sites on target cells, e.g. liver cells, in a person with type 2
diabetes. Due to the elevated levels of blood
glucose in an individual, the
β-cells (
islets of Langerhans
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...
) in the
pancreas
The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an ...
must release more insulin than normal to meet the demand and return the blood to
homeostatic
In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism an ...
levels. The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the liver cells to downregulate and decrease the number of receptors for insulin, increasing the subject's resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to
insulin. This can be seen in the continuing
gluconeogenesis in the liver even when blood glucose levels are elevated. This is the more common process of
insulin resistance
Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood sugar ...
, which leads to adult-onset diabetes.
Another example can be seen in
diabetes insipidus
Diabetes insipidus (DI), recently renamed to Arginine Vasopressin Deficiency (AVP-D) and Arginine Vasopressin Resistance (AVP-R), is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced ...
, in which the kidneys become insensitive to
arginine vasopressin
Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travel ...
.
Downregulation and upregulation in drug addiction
Family-based, adoption, and twin studies have indicated that there is a strong (50%) heritable component to vulnerability to substance abuse addiction.
Especially among genetically vulnerable individuals, repeated exposure to a drug of abuse in adolescence or adulthood causes addiction by inducing stable downregulation or upregulation in expression of specific genes and
microRNA
MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
s through
epigenetic alterations.
Such downregulation or upregulation has been shown to occur in the brain's reward regions, such as the
nucleus accumbens
The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypotha ...
.
(See, for example,
Epigenetics of cocaine addiction.)
Downregulation and upregulation in cancer
DNA damage appears to be the primary underlying cause of cancer.
If accurate DNA repair is deficient, DNA damages tend to accumulate. Unrepaired DNA damage can increase
mutational errors during
DNA replication due to error-prone
translesion synthesis
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
. DNA damage can also increase
epigenetic
In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
alterations due to errors during DNA repair.
Such mutations and epigenetic alterations can give rise to
cancer (see
malignant neoplasms
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
).
Investigation of epigenetic down- or upregulation of repaired DNA genes as possibly central to progression of cancer has been regularly undertaken since 2000.
As described in
Regulation of transcription in cancer, epigenetic downregulation of the DNA repair gene ''
MGMT'' occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40–90% of colorectal cancers and 50% of brain cancers. Similarly, epigenetic downregulation of ''
LIG4
DNA ligase 4 is an enzyme that in humans is encoded by the LIG4 gene.
Function
The protein encoded by this gene is an ATP-dependent DNA ligase that joins double-strand breaks during the non-homologous end joining pathway of double-strand break ...
'' occurs in 82% of colorectal cancers and epigenetic downregulation of ''
NEIL1
Endonuclease VIII-like 1 is an enzyme that in humans is encoded by the ''NEIL1'' gene.
NEIL1 belongs to a class of DNA glycosylases homologous to the bacterial Fpg/Nei family. These glycosylases initiate the first step in base excision repair by ...
'' occurs in 62% of
head and neck cancers and in 42% of
non-small-cell lung cancers.
Epigenetic upregulation of the DNA repair genes ''
PARP1
Poly DP-ribosepolymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly DP-ribosesynthase 1 is an enzyme that in humans is encoded by the ''PARP1'' gene. It is the most abundant of the PARP family of enzymes, accounting for 90% o ...
'' and ''
FEN1
Flap endonuclease 1 is an enzyme that in humans is encoded by the ''FEN1'' gene.
Function
The protein encoded by this gene removes 5' overhanging "flaps" (or short sections of single stranded DNA that "hang off" because their nucleotide bases a ...
'' occurs in numerous cancers (see
Regulation of transcription in cancer). ''PARP1'' and ''FEN1'' are essential genes in the error-prone and mutagenic DNA repair pathway
microhomology-mediated end joining. If this pathway is upregulated, the excess mutations it causes can lead to cancer.
PARP1
Poly DP-ribosepolymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly DP-ribosesynthase 1 is an enzyme that in humans is encoded by the ''PARP1'' gene. It is the most abundant of the PARP family of enzymes, accounting for 90% o ...
is over-expressed in tyrosine kinase-activated leukemias, in neuroblastoma, in testicular and other germ cell tumors, and in Ewing's sarcoma.
FEN1
Flap endonuclease 1 is an enzyme that in humans is encoded by the ''FEN1'' gene.
Function
The protein encoded by this gene removes 5' overhanging "flaps" (or short sections of single stranded DNA that "hang off" because their nucleotide bases a ...
is upregulated in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung.
See also
*
Regulation of gene expression
*
Desensitization (medicine)
In medicine, desensitization is a method to reduce or eliminate an organism's negative reaction to a substance or stimulus.
In pharmacology, ''drug desensitization'' refers to two related concepts. First, desensitization may be equivalent to drug ...
*
Addiction
Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use oft ...
*
Cocaine
References
Sources
* Sherwood, L. (2004). ''Human Physiology From Cells to Systems'', 5th Ed (p. 680). Belmont, CA: Brooks/Cole-Thomson Learning
* Wilmore, J., Costill, D. (2004). ''Physiology of Sport and Exercise, 3rd Ed'' (p. 164). Champaign, IL: Human Kinetics
External links
*
{{Molecular Biology
Molecular biology