Dimerization of the core domain of the p53 family: A computational study

Madhumalar, Arumugam; Jun, Lee Hui; Lane, David P.; Verma, Chandra

doi:10.4161/cc.8.1.7530

Cited by 14 publications

(10 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…59 In vitro studies with recombinant p53 DBDs carrying targeted mutations in the critical residues highlighted that the dimer interface is crucial for a long-known property of p53, called DNA binding cooperativity, H1 of the DBDs engage in intermolecular interactions to form a so-called double salt bridge as part of the DBD dimer interface. [54][55][56][57][58] This dimer interface was further confirmed when Fersht and colleagues succeeded in obtaining a structure of full-length p53 bound to DNA by using a Figure 2. role of cooperativity for DNa binding of p53 in the human genome.…”

Section: The Role Of Post-translational Modificationsmentioning

confidence: 75%

Life or death

et al. 2010

View full text Add to dashboard Cite

Section: The Role Of Post-translational Modificationsmentioning

confidence: 75%

Life or death

et al. 2010

View full text Add to dashboard Cite

“…This region encompasses H1, which forms a major part of the dimerization interface. Homodimerization of p53 is favorable, but occurs with low probability for p63 and p7352. Because dehydrons are promoters of molecular association, higher dehydron density in H1 may explain why p53 is more prone to dimerize.…”

Section: Discussionmentioning

confidence: 99%

Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds

Cino

Soares

Pedrote

et al. 2016

Sci Rep

View full text Add to dashboard Cite

The p53 family of proteins is comprised of p53, p63 and p73. Because the p53 DNA binding domain (DBD) is naturally unstable and possesses an amyloidogenic sequence, it is prone to form amyloid fibrils, causing loss of functions. To develop p53 therapies, it is necessary to understand the molecular basis of p53 instability and aggregation. Light scattering, thioflavin T (ThT) and high hydrostatic pressure (HHP) assays showed that p53 DBD aggregates faster and to a greater extent than p63 and p73 DBDs, and was more susceptible to denaturation. The aggregation tendencies of p53, p63, and p73 DBDs were strongly correlated with their thermal stabilities. Molecular Dynamics (MD) simulations indicated specific regions of structural heterogeneity unique to p53, which may be promoted by elevated incidence of exposed backbone hydrogen bonds (BHBs). The results indicate regions of structural vulnerability in the p53 DBD, suggesting new targetable sites for modulating p53 stability and aggregation, a potential approach to cancer therapy.

show abstract

“…Often some of the purported functions of p53 are overlapping and even sometimes contradictory. p53 is regulated by other transcription factors [168,169], the proteins ATM [170], MDM2 and MDMX [174-180] and other interacting proteins [181-187] and miRNAs [171-173]. Small molecule inhibitors to proteins such as MDM2 which negatively regulate p53 have been developed [56,188-190].…”

Section: Discussionmentioning

confidence: 99%

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

et al. 2011

View full text Add to dashboard Cite

Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.

show abstract

Dimerization of the core domain of the p53 family: A computational study

Cited by 14 publications

References 89 publications

Life or death

Life or death

Aggregation tendencies in the p53 family are modulated by backbone hydrogen bonds

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

Contact Info

Product

Resources

About