p53 upregulated modulator of apoptosis
The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-
Structure
The PUMA protein is part of the BH3-only subgroup of
Mechanism of action
Biochemical studies have shown that PUMA interacts with antiapoptotic Bcl-2 family members such as
Because PUMA has high affinity for binding to Bcl-2 family members, another hypothesis is that PUMA directly activates Bax and/or Bak and through Bax multimerization triggers mitochondrial translocation and with it induces apoptosis.[11][12] Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis.[13][14]
Regulation
Induction
The majority of PUMA induced
Degradation
PUMA levels are downregulated through the activation of caspase-3 and a protease inhibited by the serpase inhibitor N-tosyl-L-phenylalanine chloromethyl ketone, in response to signals such as the cytokine TGFβ, the death effector TRAIL or chemical drugs such as anisomycin.[31] PUMA protein is degraded in a proteasome dependent manner and its degradation is regulated by phosphorylation at a conserved serine residue at position 10.[32]
Role in cancer
Several studies have shown that PUMA function is affected or absent in
PUMA can also function as an indicator of p53 mutations. Many cancers exhibit mutations in the p53 gene, but this mutation can only be detected through extensive DNA sequencing. Studies have shown that cells with p53 mutations have significantly lower levels of PUMA, making it a good candidate for a protein marker of p53 mutations, providing a simpler method for testing for p53 mutations.[44]
Cancer therapeutics
Therapeutic agents targeting PUMA for
Cancer treatments
Research has shown that increased PUMA expression with or without
Resveratrol, a plant-derived stilbenoid, is currently under investigation as a cancer treatment. Resveratrol acts to inhibit and decrease expression of antiapoptotic Bcl-2 family members while also increasing p53 expression. The combination of these two mechanisms leads to apoptosis via activation of PUMA, Noxa and other proapoptotic proteins, resulting in mitochondrial dysfunction.[53]
Other approaches focus on inhibiting antiapoptotic Bcl-2 family members just as PUMA does, allowing cells to undergo apoptosis in response to cancerous activity. Preclinical studies involving these inhibitors, also described as BH3 mimetics, have produced promising results.[7][35][54]
Side-effect treatment
See also
- Apoptosis
- Apoptosome
- Bcl-2
- Bcl-2-associated X protein(BAX)
- BH3 interacting domain death agonist(BID)
- Caspases
- Cytochrome c
- Noxa
- Mitochondrion
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000105327 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000002083 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 11463392.
- ^ PMID 11572983.
- ^ PMID 19641508.
- PMID 18589438.
- PMID 12574499.
- PMID 36889945.
- ^ PMID 17127703.
- ^ PMID 18522850.
- S2CID 1223271.
- S2CID 13300521.
- PMID 18990690.
- S2CID 11175215.
- PMID 16166651.
- PMID 17237824.
- PMID 12145320.
- S2CID 43760689.
- PMID 12695333.
- PMID 14517295.
- PMID 16801400.
- PMID 18579560.
- PMID 12913114.
- S2CID 2997826.
- PMID 16772523.
- PMID 16832056.
- PMID 15452181.
- PMID 15865925.
- S2CID 19355084.
- PMID 21364664.
- S2CID 205383514.
- PMID 15865941.
- ^ PMID 17322918.
- PMID 12963126.
- S2CID 6313836.
- PMID 17267315.
- PMID 14585359.
- S2CID 35505384.
- PMID 15192153.
- PMID 17178918.
- PMID 15314031.
- PMID 21478674.
- ^ PMID 16675590.
- ^ PMID 18089712.
- ^ PMID 16481741.
- PMID 16982766.
- PMID 15960600.
- S2CID 22313616.
- S2CID 25068339.
- PMID 17904788.
- PMID 19514131.
- PMID 17921043.
- S2CID 13472437.