Suppression of tumorigenesis by the p53 target PUMA

Hemann, Michael T.; Zilfou, Jack T.; Zhao, Zhen; Burgess, Darren J.; Hannon, Gregory J.; Lowe, Scott W.

doi:10.1073/pnas.0403286101

Cited by 174 publications

(146 citation statements)

References 33 publications

(58 reference statements)

Supporting

Mentioning

135

Contrasting

Unclassified

Order By: Relevance

“…Other BH3-only proteins may also restrain neoplasia in specific cell types. RNAi to Puma accelerated Eμ-myc-driven lymphomagenesis [63]. Moreover, some aged Bad-deficient mice develop diffuse large B cell lymphoma [23] and some Bid-deficient animals succumb late in life to a chronic myeloproliferative syndrome that resembles chronic myelomonocytic leukaemia [64].…”

Section: Roles Of Bh3-only Proteins In Tumorigenesismentioning

confidence: 99%

Life in the balance: how BH3-only proteins induce apoptosis

Willis

Adams

2005

Current Opinion in Cell Biology

676

581

View full text Add to dashboard Cite

BH3-only members of the Bcl-2 intracellular protein family, which include Bim, Bmf, Bik, Bad, Bid, Puma, Noxa and Hrk, mediate many developmentally programmed and induced cytotoxic signals. They have key roles in development, tissue homeostasis, immunity and tumor suppression, and compounds mimicking them are promising anti-cancer agents. Their activity is normally constrained by transcriptional and/or diverse post-transcriptional controls. When activated, these death ligands engage pro-survival Bcl-2-like proteins via the BH3 domain, inactivating their function. Bim and Puma bind all the pro-survival proteins, whereas others, such as Noxa and Bad, engage distinct subsets and exhibit complementary killing. Hence, multiple pro-survival proteins must be inactivated to unleash Bax and Bak, which drive apoptosis. Whether certain BH3-only proteins also directly activate Bax/Bak remains controversial.

show abstract

Section: Roles Of Bh3-only Proteins In Tumorigenesismentioning

confidence: 99%

Life in the balance: how BH3-only proteins induce apoptosis

Willis

Adams

2005

Current Opinion in Cell Biology

676

581

View full text Add to dashboard Cite

show abstract

“…and Ras oncogenes 300 . Noxa has been shown to be upregulated in melanoma in response to proteasome inhibition resulting in cells becoming re-sensitized to apoptosis 301 , although again there is no evidence that loss of Noxa causes carcinogenesis.…”

Section: The Role Of Bh3-only Proteins In Melanomamentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

show abstract

“…These findings suggest that both a reduction/expansion of hematopoietic stem/progenitor cell numbers and death of leukocytes are required for PUMA-mediated DNA damage associated lymphoma development (Figure 1d). Somewhat paradoxically, loss of PUMA conversely accelerates c-Myc-induced lymphomagenesis, as well as chemical-mediated intestinal tumorigenesis in mice (Hemann et al, 2004;Michalak et al, 2009;Qiu et al, 2009). c-Myc controls the balance between hematopoietic stem/progenitor cell self-renewal and differentiation The prototypical DAMP, high-mobility group box 1 protein (HMGB1) binds to several receptors including the receptor for advanced glycation end products (RAGE) and sustains inflammation, cell proliferation and autophagy, which in turn promote tumor growth.…”

mentioning

confidence: 99%