Sandbox Reserved 428: Difference between revisions
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==Introduction== | ==Introduction== | ||
<br> | <br> | ||
The | The <scene name='48/483885/Color1/6'>vitamin d receptor</scene> (VDR) is a ligand-dependent transcriptional regulator with two strands. VDR belongs to the superfamily of nuclear receptors which control homeostasis, cell differentiation and growth, and many physiological processes. All proteins that belong to the nuclear receptor superfamily have a variable N-terminus region (A/B region), a hinge region that is flexible (D region), a conserved DNA-binding region (DBD, C region), and a moderately conserved ligand-binding region (LBD, E/F region). In the case of VDR, the A/B region is very short so it does not have any AF-1 function and the ligand binding region has a dimerization interface and a transcriptional activation domain that is ligand-dependent (AF-2).[1] <br> <br> | ||
The VDR has both an active and suppressed form. The activation or suppression function is caused by the binding of the DR3 response element as a heterodimer with the retinoid X receptor of the target genes. Due to the interactions with the basal transcriptional machinery and transcriptional cofactors, transcription is either activated or suppressed. When VDR is in its active form it regulates both phosphate and calcium metabolism, has immunosuppressive effects, and induces cell differentiation. When there are defects in the VDR that effect its metabolism it can lead to diseases such as severe rickets, secondary hyperparathyroidism, and hypocalcemia. Though defects in VDR can cause many diseases, fully functioning VDR can be used as treatment for disease such as cancer, autoimmune disease, psoriasis, osteoporosis, and renal osteodystrophy.[1] | The VDR has both an active and suppressed form. The activation or suppression function is caused by the binding of the DR3 response element as a heterodimer with the retinoid X receptor of the target genes. Due to the interactions with the basal transcriptional machinery and transcriptional cofactors, transcription is either activated or suppressed. When VDR is in its active form it regulates both phosphate and calcium metabolism, has immunosuppressive effects, and induces cell differentiation. When there are defects in the VDR that effect its metabolism it can lead to diseases such as severe rickets, secondary hyperparathyroidism, and hypocalcemia. Though defects in VDR can cause many diseases, fully functioning VDR can be used as treatment for disease such as cancer, autoimmune disease, psoriasis, osteoporosis, and renal osteodystrophy.[1] | ||
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==Additional Features== | ==Additional Features== | ||
Hereditary Vitamin D resistant rickets (HVDRR) is a condition that mostly occurs in children and results in soft and weak bone formation, which often causes deformities in bone. A lack of proper nutrients, Vitamin D in particular, as well as defects in the Vitamin D receptor can cause rickets in humans. This can occur when the VDR is impaired in its ability to activate transcription in response to the 1,25-(OH)2D3 ligand [1]. VDR regulates the hormonal form of Vitamin D, through modifying the transcription of the target to a certain sequence of DNA, called the Vitamin D responsive element (VDRE). This activation requires an additional receptor, which is a Retinoid X Receptor (RXR) to bind to the heterodimer [1]. A mutation in the transcription of the protein has the potential to result in the disease known as type 2 rickets. The mutation results in the <scene name='48/483885/Heterodimer/1'> | Hereditary Vitamin D resistant rickets (HVDRR) is a condition that mostly occurs in children and results in soft and weak bone formation, which often causes deformities in bone. A lack of proper nutrients, Vitamin D in particular, as well as defects in the Vitamin D receptor can cause rickets in humans. This can occur when the VDR is impaired in its ability to activate transcription in response to the 1,25-(OH)2D3 ligand [1]. VDR regulates the hormonal form of Vitamin D, through modifying the transcription of the target to a certain sequence of DNA, called the Vitamin D responsive element (VDRE). This activation requires an additional receptor, which is a Retinoid X Receptor (RXR) to bind to the heterodimer [1]. A mutation in the transcription of the protein has the potential to result in the disease known as type 2 rickets. The mutation results in the <scene name='48/483885/Heterodimer/1'>heterodimer</scene> not forming properly. The failure in the transcription of this process from the failing of the binding of the heterodimer can cause this disease. Current research shows that there are two mechanisms that can cause Rickets to occur within the body. The first is a point mutation of an amino acid in the zinc finger region of the VDR that reduces the binding of the heterodimer, which is found in the residues 21-85 [1]. The other is a premature stop codon in the DNA sequences that does not allow for the full transcription, which can have an effect of reducing the affinity of the heterodimer binding [1]. | ||
It has been shown that VDR has an effect on the hair folicle cycle through the elimination of the receptor. In null-VDR mice, it has been shown that with normal mineral ion levels that the mice result in alopecia, disease inducing hair loss [2]. VDR is expressed in the hair follicle keratinocytes and its levels are higher in the late anagen and catagen stages of the hair cycle [2]. These two stages are vital in the differentiation and proliferation of hair follicle keratinocytes, which regulate hair growth in the body. Much research has been done into the mechanism in which the VDR effects the hair follicle cycle with the overall mechanism still unknown. The mechanism was first believed that the binding of VDR to 1,25- dihydroxyvitamin D causing transactivation due to the fact that targeted expressions of wild-type VDR to the keratinocytes of VDR null mice rescued alopecia [2]. Although, this was disproven through investigations in vitamin D-deficient mice that had no detectable 1,25-dihydroxyvitamin D for the VDR to bind, yet the mice did not develop alopecia. This shows that the VDR transcriptional activation of DNA is not the main cause of the loss of hair follicles. Current research observes the ligand-independent actions of the VDR that have not been observed extensively as a mechanism [2]. Nuclear receptor co-repressor genes have been observed in studies to have an effect on the hair follicle cycle including the HR gene (Hairless). This corepressor has been shown to have interactions with the VDR in vivo and tests with the mutation of Hairless have caused alopecia in mice in vivo [2]. Thus, although the mechanism behind the interaction of Hairless and the VDR is still unknown it has been shown in studies that there is a relationship between the two and alopecia. | It has been shown that VDR has an effect on the hair folicle cycle through the elimination of the receptor. In null-VDR mice, it has been shown that with normal mineral ion levels that the mice result in alopecia, disease inducing hair loss [2]. VDR is expressed in the hair follicle keratinocytes and its levels are higher in the late anagen and catagen stages of the hair cycle [2]. These two stages are vital in the differentiation and proliferation of hair follicle keratinocytes, which regulate hair growth in the body. Much research has been done into the mechanism in which the VDR effects the hair follicle cycle with the overall mechanism still unknown. The mechanism was first believed that the binding of VDR to 1,25- dihydroxyvitamin D causing transactivation due to the fact that targeted expressions of wild-type VDR to the keratinocytes of VDR null mice rescued alopecia [2]. Although, this was disproven through investigations in vitamin D-deficient mice that had no detectable 1,25-dihydroxyvitamin D for the VDR to bind, yet the mice did not develop alopecia. This shows that the VDR transcriptional activation of DNA is not the main cause of the loss of hair follicles. Current research observes the ligand-independent actions of the VDR that have not been observed extensively as a mechanism [2]. Nuclear receptor co-repressor genes have been observed in studies to have an effect on the hair follicle cycle including the HR gene (Hairless). This corepressor has been shown to have interactions with the VDR in vivo and tests with the mutation of Hairless have caused alopecia in mice in vivo [2]. Thus, although the mechanism behind the interaction of Hairless and the VDR is still unknown it has been shown in studies that there is a relationship between the two and alopecia. | ||