The transcription-independent mitochondrial cell death pathway is defective in non-transformed cells containing the Pro47Ser variant of p53

Cancer Biology & Therapy
Anna Budina-KolometsMaureen E Murphy

Abstract

Approximately half of all human cancers contain mutations in the TP53 tumor suppressor. In addition to mutations, there are single nucleotide polymorphisms (SNPs) in TP53 that can dampen p53 function, and can increase cancer risk and decrease the efficacy of cancer therapy. Approximately 6% of Africans and 1% of African-Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser, or S47). The S47 variant is associated with increased breast cancer risk in pre-menopausal African Americans, and in a mouse model for the S47 variant, mice are predisposed to spontaneous cancers. We recently showed that the S47 variant is impaired for p53-mediated apoptosis in response to radiation and some genotoxic agents, particularly cisplatin. Here we identify the mechanism for impaired apoptosis of S47 in response to cisplatin. We show that following cisplatin treatment, the S47 variant shows normal stabilization and serine 15 phosphorylation, but reduced ability to bind to the peptidyl prolyl isomerase PIN1, which controls the mitochondrial localization of p53. This is accompanied by impaired mitochondrial localization of S47, along with decreased induction of cleaved caspase-3. Interestingly, we show that this defe...Continue Reading

References

Oct 25, 2002·Nature·Hongwu ZhengZhi-Xiong Jim Xiao
Feb 5, 2003·Nature Genetics·Patrick DumontMaureen Murphy
Apr 2, 2003·Molecular Cell·Motohiro MiharaUte M Moll
Apr 13, 2004·Nature Cell Biology·J I-Ju LeuDonna L George
Apr 27, 2005·The Journal of Biological Chemistry·Xiaoxian LiMaureen E Murphy
Oct 18, 2005·Current Opinion in Cell Biology·Ute M MollWolfgang Deppert
May 17, 2007·Apoptosis : an International Journal on Programmed Cell Death·Paloma BragadoAlmudena Porras
Jun 6, 2009·The Journal of Biological Chemistry·Stephen M SykesSteven B McMahon
Aug 4, 2010·Cold Spring Harbor Perspectives in Biology·Rachel Beckerman, Carol Prives
Oct 21, 2011·Proceedings of the National Academy of Sciences of the United States of America·Alice GrisonGiannino Del Sal
Jun 21, 2012·Genes & Development·William A Freed-Pastor, Carol Prives
Sep 1, 2012·Cell Death and Differentiation·G SorrentinoG Del Sal
Mar 8, 2016·Cell Reports·Che-Pei KungMaureen E Murphy
Apr 3, 2016·Cold Spring Harbor Perspectives in Medicine·Subhasree Basu, Maureen E Murphy
Aug 4, 2016·Cell Cycle·Subhasree BasuMaureen E Murphy
Sep 11, 2016·The Journal of Endocrinology·Che-Pei Kung, Maureen E Murphy
Jun 27, 2017·NPJ Breast Cancer·Maureen E MurphyChristine B Ambrosone
Sep 25, 2017·Cell Death and Differentiation·Cédric CastrogiovanniPatrick Dumont
Feb 22, 2018·Genes & Development·Subhasree BasuMaureen E Murphy
Apr 27, 2018·Frontiers in Endocrinology·Keerthana GnanapradeepanMaureen E Murphy
Jan 1, 2018·Cell Death and Differentiation·Cédric CastrogiovanniPatrick Dumont

❮ Previous
Next ❯

Citations

Jun 4, 2019·Journal of Molecular Cell Biology·Thibaut BarnoudMaureen E Murphy

❮ Previous
Next ❯

Methods Mentioned

BETA
proximity ligation assay
acetylation

Software Mentioned

GraphPad Prism

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Breast Cancer: Therapeutic Approaches

Several different therapeutic approaches are used to treat breast cancer. These include chemotherapy, hormonal therapy, targeted therapy, and Immunotherapy. Discover the latest research on breast cancer therapeutic approaches here.