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AR-V7: Androgen Receptor Variant 7 - Coggle Diagram
AR-V7: Androgen Receptor Variant 7
1 Genesis
Androgen Receptor (AR) is Normal: The AR itself is a normal protein present in various cells, including prostate cells. Its primary function is to mediate the effects of androgens (male sex hormones like testosterone).
Gene Targets Can Vary: The specific genes that the Androgen Receptor activates depend on the cell type and context. In normal prostate cells, Androgen receptor activation leads to the expression of genes involved in normal prostate development and function.
Abnormal Gene Activation in Cancer: In prostate cancer cells, the Androgen Receptor can become dysregulated or overactive. It might bind to DNA sequences it wouldn't normally bind to, or it might activate genes to a much higher degree than usual. This abnormal gene activation can lead to the expression of genes that promote uncontrolled cell growth, survival, and other hallmarks of cancer.
2 Androgen Deprivation Therapy
Normal Androgen Receptor (AR) Signaling
Androgens (like testosterone) bind to the Androgen Receptor in the cytoplasm.
This binding triggers a conformational change in the receptor, allowing it to translocate to the nucleus.
In the nucleus of these cancer cells, the Androgen Receptor binds to specific DNA sequences, activating the transcription of genes that promote prostate cancer cell growth and survival.
Androgen Deprivation Therapy aims to reduce androgen levels, thereby depriving prostate cancer cells of this growth signal.
3 Mutated Receptor
AR-V7 and Resistance to Androgen Deprivation Therapy
AR-V7 is a constitutively active variant of the Androgen Receptor, meaning it's always "on" even in the absence of androgens.
It lacks the ligand-binding domain that is normally targeted by Androgen Deprivation Therapy and Androgen Receptor Signaling Inhibitors drugs.
AR-V7 can still translocate to the nucleus and activate gene transcription, promoting cancer cell growth even when androgen levels are low.
This makes AR-V7 a major driver of resistance to Androgen Deprivation Therapy and Androgen Receptor Signaling Inhibitor therapy.
4 Alternative Splicing
mechanism
PAK1/NF-κB Pathway and AR-V7 Production
PAK1 (p21-activated kinase 1) is overexpressed in some prostate cancers.
PAK1 activates the NF-κB signaling pathway.
NF-κB increases the expression of hnRNPA1, a splicing factor.
hnRNPA1 promotes alternative splicing of the AR gene, leading to increased production of AR-V7.In the context of the research article, PAK1 and the NF-κB pathway influence this alternative splicing process by increasing the expression of a splicing factor called hnRNPA1. This ultimately leads to more AR-V7 being produced, driving resistance to Androgen Receptor Signaling Inhibitors drugs.
What is it
Normal Splicing: Genes are made up of coding regions (exons) and non-coding regions (introns). During normal splicing, introns are removed and exons are joined together to create the final messenger RNA (mRNA) that is then translated into a protein.
Alternative Splicing: This is a process where different combinations of exons are joined together, leading to the production of multiple different mRNA transcripts (and thus, different protein isoforms) from a single gene.
AR-V7 Production: In the case of AR-V7, alternative splicing of the androgen receptor (AR) gene results in an mRNA transcript that lacks the ligand-binding domain (the part that normally binds to androgens like testosterone). This creates a truncated protein (AR-V7) that is constitutively active (meaning it's always "on") even without androgens.
5 The Bottom Line
Androgen Deprivation Therapy and Androgen Receptor Signaling Inhibitors drugs work by blocking the binding of androgens to the Androgen Receptor or preventing the Androgen Receptor from functioning in the nucleus.
However, AR-V7 bypasses these mechanisms because it doesn't require androgens to be active and can still function in the nucleus even when the full-length Androgen Receptor is inhibited.
This allows prostate cancer cells to continue growing and surviving despite Androgen Deprivation Therapy or Androgen Receptor Signaling Inhibitors therapy, leading to treatment resistance and disease progression.