PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications.

After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria.

[7][30] 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.

Additionally, many human tumors contain p53 mutations,[33] which results in no induction of PUMA, even after DNA damage induced through irradiation or chemotherapy drugs.

[34] Other cancers, which exhibit overexpression of antiapoptotic Bcl-2 family proteins, counteract and overpower PUMA-induced apoptosis.

[39][40][41][42][43] Inhibiting PUMA induced apoptosis may be an interesting target for reducing the side effects of cancer treatments, such as chemotherapy, which induce apoptosis in rapidly dividing healthy cells in addition to rapidly dividing cancer cells.

[7] Research has shown that increased PUMA expression with or without chemotherapy or irradiation is highly toxic to cancer cells, specifically lung,[45] head and neck,[46] esophagus,[47] melanoma,[48] malignant glioma,[49] gastric glands,[50] breast[51] and prostate.

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.