A Guide to PIN1 Function and Mutations Across Cancers

Boustani, Maguie El; Stefano, Lucía De; Caligiuri, Isabella; Mouawad, Nayla; Granchi, Carlotta; Canzonieri, Vincenzo; Tuccinardi, Tiziano; Giordano, Antonio; Rizzolio, Flavio

doi:10.3389/fphar.2018.01477

Cited by 18 publications

(24 citation statements)

References 93 publications

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“…PIN1 is a prolyl isomerase that causes a cis-trans or trans-cis conformational change at proline resides that follow phosphorylated serine/threonine sites (pS/T-P sites) [142]. PIN1 isomerization has significant effects on the localization, stability, and activation of target proteins that regulate a variety of cellular processes including proliferation, survival, and epithelial-to-mesenchymal transition [143].…”

Section: Pin1 Inhibitionmentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

134

110

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MYC is a master transcriptional regulator that controls almost all cellular processes. Over the last several decades, researchers have strived to define the context-dependent transcriptional gene programs that are controlled by MYC, as well as the mechanisms that regulate MYC function, in an effort to better understand the contribution of this oncoprotein to cancer progression. There are a wealth of data indicating that deregulation of MYC activity occurs in a large number of cancers and significantly contributes to disease progression, metastatic potential, and therapeutic resistance. Although the therapeutic targeting of MYC in cancer is highly desirable, there remain substantial structural and functional challenges that have impeded direct MYC-targeted drug development and efficacy. While efforts to drug the 'undruggable' may seem futile given these challenges and considering the broad reach of MYC, significant strides have been made to identify points of regulation that can be exploited for therapeutic purposes. These include targeting the deregulation of MYC transcription in cancer through small-molecule inhibitors that induce epigenetic silencing or that regulate the G-quadruplex structures within the MYC promoter. Alternatively, compounds that disrupt the DNA-binding activities of MYC have been the long-standing focus of many research groups, since this method would prevent downstream MYC oncogenic activities regardless of upstream alterations. Finally, proteins involved in the post-translational regulation of MYC have been identified as important surrogate targets to reduce MYC activity downstream of aberrant cell stimulatory signals. Given the complex regulation of the MYC signaling pathway, a combination of these approaches may provide the most durable response, but this has yet to be shown. Here, we provide a comprehensive overview of the different therapeutic strategies being employed to target oncogenic MYC function, with a focus on post-translational mechanisms.

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Section: Pin1 Inhibitionmentioning

confidence: 99%

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Allen-Petersen¹,

Sears²

2019

BioDrugs

134

110

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“…The association of variants with specific diseases is outside the scope of this review. However, the interested reader is referred to an excellent review on single nucleotide polymorphisms and mutations of Pin1 in cancers [23]. Many other articles exist discussing the role of Pin1 in cancer and Alzheimer's disease, for example references [20,21,[24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Activity and Affinity of Pin1 Variants

2019

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Pin1 is a peptidyl-prolyl isomerase responsible for isomerizing phosphorylated S/T-P motifs. Pin1 has two domains that each have a distinct ligand binding site, but only its PPIase domain has catalytic activity. Vast evidence supports interdomain allostery of Pin1, with binding of a ligand to its regulatory WW domain impacting activity in the PPIase domain. Many diverse studies have made mutations in Pin1 in order to elucidate interactions that are responsible for ligand binding, isomerase activity, and interdomain allostery. Here, we summarize these mutations and their impact on Pin1 s structure and function.

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“…Pin1 is a peptidyl-prolyl cis-trans isomerase (PPIase) able to isomerise p-serine/p-threonine-proline sequences thus effecting conformational change which alters the activity of its target proteins (95). It is highly expressed in many cancers (96,97) and facilitates activation of the PI3K/Akt pathway. One way it does this is by increasing Akt stability through serine 473 phosphorylation (98).…”

Section: Peptidyl-prolyl Cis-trans Isomerasementioning

confidence: 99%

Mini Review: Opposing Pathologies in Cancer and Alzheimer's Disease: Does the PI3K/Akt Pathway Provide Clues?

et al. 2020

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This minireview is a brief overview examining the roles of insulin-like growth factors (IGFs) and the PI3K/Akt pathway in two apparently unconnected diseases: Alzheimer's dementia and cancer. For both, increased age is a major risk factor, and, in accord with the global rise in average life expectancy, their prevalence is also increasing. Cancer, however, involves excessive cell proliferation and metastasis, whereas Alzheimer's disease (AD) involves cell death and tissue destruction. The apparent "inverse" nature of these disease states is examined here, but also some important commonalities in terms of the PI3K/Akt pathway, glucose utilization and cell deregulation/death. The focus here is on four key molecules associated with this pathway; notably, the insulin receptor substrate 1 (IRS-1), cellular tumor antigen p53 (p53), peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) and low-density lipoprotein receptor-related protein-1 (LRP1), all previously identified as potential therapeutic targets for both diseases. The insulin-resistant state, commonly reported in AD brain, results in neuronal glucose deprivation, due to a dampening down of the PI3K/Akt pathway, including overactivity of the mammalian target of rapamycin 1 (mTORC1) complex, hyperphosphorylation of p53 and neuronal death. This contrasts with cancer, where there is overstimulation of the PI3K/Akt pathway and the suppression of mTORC1 and p53, enabling abundant energy and unrestrained cell proliferation. Although these disease states appear to be diametrically opposed, the same key molecules are controlling pathology and, with differential targeting of therapeutics, may yet provide a beneficial outcome for both.

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A Guide to PIN1 Function and Mutations Across Cancers

Cited by 18 publications

References 93 publications

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

Activity and Affinity of Pin1 Variants

Mini Review: Opposing Pathologies in Cancer and Alzheimer's Disease: Does the PI3K/Akt Pathway Provide Clues?

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