UniProt release 2013_11
Published November 13, 2013
Forever young and cancer-free… in a black hole
In east African grasslands and savannas lives a most bizarre rodent: the naked mole-rat (Heterocephalus glaber). Naked mole-rats are small burrowing rodents, about the size of a mouse. They inhabit underground tunnels, where they form colonies ranging in size from 20 to 300 individuals. Naked mole-rats exhibit eusociality, a lifestyle reminiscent of that of ants or some bees. The colony is ruled by a queen; it has 1 to 3 males who breed only with the queen, while the other female members of the colony are sterile workers or soldiers. But this is not the only singularity of this amazing mammal. Among many other unexpected features, naked mole rats exhibit exceptional longevity, some reaching ages of 30 years, about 10 times longer than ordinary mice (in a protected environment). They show negligible senescence, no age-related increase in mortality, and high fecundity until death. In addition, they are highly resistant to cancer.
In 2009, it was reported that naked mole rats may resist cancer thanks to an extremely efficient mechanism of cell contact inhibition, called early contact inhibition (ECI). Contact inhibition is a process that arrests cell growth when cells come in contact with each other or the extracellular matrix. It is a powerful anticancer mechanism. The process of ECI causes naked mole-rat cells to arrest at a much lower density than mouse cells, and the loss of ECI makes naked mole-rat cells more susceptible to malignant transformation.
When culturing naked mole-rat fibroblasts, Tian et al. observed that the culture media became very viscous after a few days, much more than the media conditioned by human, guinea-pig or mouse cells. This increase in viscosity was due to the increased production of an anionic, nonsulfated glycosaminoglycan: high-molecular-mass hyaluronan (HMM-HA). HMM-HA overproduction was not restricted to tissue culture conditions. It was also observed in vivo, including in brain, heart, kidney and skin. Increased HMM-HA production was due to robust synthesis, via the up-regulation of hyaluronan synthase 2 (Has2), the enzyme catalyzing HMM-HA production, combined with slower degradation, due to the down-regulation of HA-degrading enzyme.
Secreted HMM-HA binds to fibroblasts through the Cd44 cell surface receptor and triggers intracellular signaling, leading to the expression of the cyclin-dependent kinase inhibitor Cdkn2a/p16-INK4a and to the induction of ECI. In naked mole-rat cells, this signaling is further optimized, since these cells exhibit a 2-fold higher affinity for HA as compared to mouse or human cells.
HA is widely distributed and one of the main components of the extracellular matrix. The authors hypothesized that the increased HMM-HA production in the naked mole-rat could have evolved as an adaptation to a subterranean lifestyle to provide flexible skin needed to squeeze through underground tunnels. This adaptation to harsh living conditions would turn out to have additional benefits, such as contributing to cancer resistance.
As of this release, naked mole-rat Has2 has been manually annotated and is publicly available in UniProtKB/Swiss-Prot entry G5AY81.
Changes to the controlled vocabulary of human diseasesNew diseases:
- Amyotrophic lateral sclerosis 19
- Cardiomyopathy, dilated 1MM
- Combined oxidative phosphorylation deficiency 16
- Cortical dysplasia, complex, with other brain malformations 2
- Cortical dysplasia, complex, with other brain malformations 3
- Cortical dysplasia, complex, with other brain malformations 4
- Deafness, autosomal recessive, 88
- Dyschromatosis universalis hereditaria 3
- Epilepsy, familial adult myoclonic, 5
- Immunodeficiency 8
- Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 3
- Left ventricular non-compaction 9
- Left ventricular non-compaction 10
- Meckel syndrome 11
- Multiple congenital anomalies-hypotonia-seizures syndrome 3
- Myopia 22, autosomal dominant
- Paroxysmal nocturnal hemoglobinuria 2
- Retinitis pigmentosa with or without situs inversus
- Spermatogenic failure 12
- CD59 deficiency -> Hemolytic anemia, CD59-mediated, with or without polyneuropathy
- Cortical dysplasia complex with other brain malformations -> Cortical dysplasia, complex, with other brain malformations 1
- Dyschromatosis symmetrical hereditaria -> Dyschromatosis symmetrica hereditaria 1
- Dyskeratosis congenita, X-linked recessive -> Dyskeratosis congenita, X-linked
- Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia -> Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1
- Myopia 21 -> Myopia 21, autosomal dominant
- Paroxysmal nocturnal hemoglobinuria -> Paroxysmal nocturnal hemoglobinuria 1
- Renal-hepatic-pancreatic dysplasia -> Renal-hepatic-pancreatic dysplasia 1
- Torg-Winchester syndrome -> Multicentric osteolysis, nodulosis, and arthropathy
- Epileptic encephalopathy, Lennox-Gastaut type
- Knobloch syndrome 2
Changes to the controlled vocabulary for PTMsNew term for the feature key ‘Modified residue’ (‘MOD_RES’ in the flat file):
- N-acetylated lysine
- 5-glutamyl N2-arginine -> 5-glutamyl N2-ornithine
- 5-glutamyl N2-glutamate -> 5-glutamyl glutamate