First of 4 functional domains which are

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First of all, AR (androgen receptor)mediated signalling pathway is crucial to maintain the normal function ofprostate, the spermatogenesis. Testosterone is generated by testes which thentranslocated to cytoplasm. When this steroid hormone is entered into cytoplasm,the conversion into dihydrotestosterone (DHT) is promoted by 5?-reductase,cytochrome P450 enzyme (da Silva et al.

, 2013). DHT can bind to AR whichactivates the signalling pathway after migrated into nucleus.  AR is one of the steroid hormone receptorswhereby it is composed of 4 functional domains which are N-terminal domain (NTD),deoxyribonucleic acid-binding domain (DBD), ligand-binding domain (LBD) andshort amino acid sequence. The role of NTD is acts as transcription activatorwhile DBD is to maintain integrity of the dimerization and to stabilize AR-DNAcomplex (Ramalingam, Ramamurthy and Njar, 2017).

LBD is the site which allowsthe steroid hormone to act on and short amino acid consists of hinge regionwhich segregate the LBD from DBD, including the function of ligand-dependentnuclear localization signal (NLS) for AR nuclear transport (Ramalingam,Ramamurthy and Njar, 2017). When there is no ligand, AR remains in thecytoplasm and associated with heat shock proteins and other chaperones. Viceversa, when ligand binds to AR, this complex will trigger alteration in conformationof LBD, and this fosters the intramolecular and intermolecular interactionbetween N-terminal and C-terminal domains (Ramalingam, Ramamurthy and Njar,2017). As a result, dimerization, phosphorylation and nuclear translocation canoccur. The complex within ligand and AR will recognize and bind to androgenresponse elements (ARE) in promoter and enhancer regions of target genes which promotegene expression involved in proliferation and maintenance of prostate. The occurrence of prostate cancer is contributed byderegulation of AR signalling.

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Most of the time, prostate cancer progression iscaused by overexpression of AR which triggered by aberrant post-translationalmodification, generation of AR splice variants and so on (Ramalingam,Ramamurthy and Njar, 2017). There are numerous of DHT-AR complex formed in thecytoplasm whereby it will increase frequency of expression of AR when theymigrated into nucleus. This will fasten the cell proliferation by the higherrate of transcription activation. Next, formation of ligand-independent AR alsowill lead to higher rate of survival cell production. Due to the cross-talkpathway, the activated AKT will initiate formation of AR to be activated andmoved into nucleus which then bind on ARE and the gene transcription can beginand make the cancerous cell to divide continuously. At last, AR molecule in thecytosol can be undergo mutation which cause other ligand can be bind with. Thisalso raises AR activity drastically in prostate environment and promotes theformation of mutated but activated complex, can migrate into nucleus. All thesefactors lead to proliferation and growth rate to be increased which then galvanizeAR activation and then develop into prostate cancer.


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