Lin-28 homolog A is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''LIN28''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
LIN28 encodes an
RNA-binding protein
that binds to and enhances the translation of the
IGF-2
Insulin-like growth factor 2 (IGF-2) is one of three protein hormones that share structural similarity to insulin. The MeSH definition reads: "A well-characterized neutral peptide believed to be secreted by the liver and to circulate in the b ...
(insulin-like growth factor 2)
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the ...
.
Lin28 binds to the
let-7 pre-
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. mi ...
and blocks production of the mature let-7 microRNA in mouse
embryonic stem cell
Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist ...
s.
In
pluripotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta.
According to Latin terms, Pluripotentia means the ability for many thin ...
embryonal
carcinoma cells, LIN28 is localized in the
ribosomes
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
,
P-bodies
P-bodies, or processing bodies are distinct foci formed by phase separation within the cytoplasm of the eukaryotic cell consisting of many enzymes involved in mRNA turnover. P-bodies are highly conserved structures and have been observed in so ...
and
stress granules.
Function
Stem cell expression
LIN28 is thought to regulate the self-renewal of
stem cells. In ''
Caenorhabditis elegans'', there is only one Lin28 gene that is expressed and in vertebrates, there are two paralogs present, Lin28a and
Lin28b. In
nematodes, the LIN28
homolog
In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...
lin-28 is a
heterochronic gene that determines the onset of early larval stages of developmental events in ''C. elegans'', by regulating the self-renewal of nematode stem cells in the skin (called seam cells) and
vulva
The vulva (plural: vulvas or vulvae; derived from Latin for wrapper or covering) consists of the external female sex organs. The vulva includes the mons pubis (or mons veneris), labia majora, labia minora, clitoris, vestibular bulbs, vulv ...
(called VPCs) during development.
In mice, LIN28 is highly expressed in mouse embryonic stem cells and during early
embryogenesis.
LIN28 is highly expressed in human embryonic stem cells
and can enhance the efficiency of the formation of induced pluripotent stem (
iPS
IPS, ips, or iPS may refer to:
Science and technology Biology and medicine
* ''Ips'' (genus), a genus of bark beetle
* Induced pluripotent stem cell or iPS cells
* Intermittent photic stimulation, a neuroimaging technique
* Intraparietal sulcus, ...
) cells from human
fibroblasts.
Puberty
LIN28 overexpression in mice can cause
gigantism and a delay in
puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a bo ...
onset, consistent with human
genome-wide association studies
In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varian ...
suggesting that polymorphisms in the human LIN28B gene are associated with human height and
puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a bo ...
timing.
Mutations in LIN28B are associated with
precocious puberty
In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...
.
LIN28 can regulate glucose homeostasis in mammals by increasing
insulin-
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
-
mTOR
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
signaling and insulin sensitivity, thereby promoting resistance to high fat diet-induced
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
and type 2
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
.
Aberrant expression of LIN28 has been seen to regulate aerobic glycolysis to facilitate cancer proliferation
Tissue regeneration
Mice genetically altered to produce LIN28 during their lifespan showed improved
hair growth
The growth of human hair occurs everywhere on the body except for the soles of the feet, the inside of the mouth, the lips, the backs of the ears, the palms of the hands, some external genital areas, the navel, scar tissue, and, apart from eyela ...
[
*] and healthy tissue regeneration on added puncture wounds
in later life stages.
While the mice could regenerate limbs, they could not repair damaged heart tissue. Appropriate drugs replicated the regeneration in unaltered mice, using the same metabolic paths. The drugs increased the subjects' metabolic rates, evidently causing the body to heal at higher rates. The effects of Lin28a activation faded with age.
Structure
Models of Lin28/let-7 complexes obtained through
X-ray crystallography
X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
and
NMR
Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with ...
reveal that two folded domains of Lin28 recognize two distinct
RNA regions.
The domains are sufficient for inhibition of let-7 ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
''.
[; ]
Applications
LIN28 is a marker of undifferentiated human embryonic
stem cells
and has been used to enhance the efficiency of the formation of iPS cells from human
fibroblasts.
References
Further reading
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External links
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{{PDB Gallery, geneid=79727