Protein Kinase C δ Overexpressing Transgenic Mice Are Resistant to Chemically but not to UV Radiation–Induced Development of Squamous Cell Carcinomas: A Possible Link to Specific Cytokines and Cyclooxygenase-2

Aziz, Moammir H.; Wheeler, Deric L.; Bhamb, Bhushan; Verma, Ajit Kumar

doi:10.1158/0008-5472.can-05-2684

Cited by 34 publications

(24 citation statements)

References 45 publications

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“…Similar to wildtype MEFs, KCs are highly sensitive to caffeine treatment after UV irradiation (46,47). Thus, KCs lacking PKC␦, such as in squamous papillomas and carcinomas, are also likely to have this dual defect in the response to DNA damage, resulting in both reduced cell cycle arrest and reduced apoptosis (23,24,48).…”

Section: Discussionmentioning

confidence: 99%

The Protein Kinase Cδ Catalytic Fragment Is Critical for Maintenance of the G2/M DNA Damage Checkpoint

LaGory

Sitailo

Denning

2010

Journal of Biological Chemistry

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Protein kinase C␦ (PKC␦) is an essential component of the intrinsic apoptotic program. Following DNA damage, such as exposure to UV radiation, PKC␦ is cleaved in a caspase-dependent manner, generating a constitutively active catalytic fragment (PKC␦-cat), which is necessary and sufficient for keratinocyte apoptosis. We found that in addition to inducing apoptosis, expression of PKC␦-cat caused a pronounced G 2 /M cell cycle arrest in both primary human keratinocytes and immortalized

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Section: Discussionmentioning

confidence: 99%

The Protein Kinase Cδ Catalytic Fragment Is Critical for Maintenance of the G2/M DNA Damage Checkpoint

LaGory

Sitailo

Denning

2010

Journal of Biological Chemistry

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“…Experiments with transgenic mice overexpressing specific PKC isozymes suggest that loss of PKC could contribute to the tumor-promoting properties of phorbol esters. PKCδ overexpression in the epidermis of mice protects them from chemically induced development of squamous carcinomas (Reddig et al 1999; Aziz et al 2006); PKCε overexpression in the epidermis reduced papilloma burden by 95% compared to wild-type controls, but enhanced carcinomas (Reddig et al 2000). Mice overexpressing PKCα in their epidermis were reported not to affect susceptibility to skin tumor promotion (Wang HQ and Smart 1999).…”

Section: Phorbol Esters Tumor Promotion and Down-regulationmentioning

confidence: 99%

Protein kinase C: perfectly balanced

Newton

2018

Critical Reviews in Biochemistry and Molecular Biology

231

224

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Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are ‘receptors’ for the potent tumor-promoting phorbol esters. This set in place a concept that PKC isozymes are oncoproteins. Yet three decades of cancer clinical trials targeting PKC with inhibitors failed and, in some cases, worsened patient outcome. Emerging evidence from cancer-associated mutations and protein expression levels provide a reason: protein kinase C isozymes generally function as tumor suppressors and their activity should be restored, not inhibited, in cancer therapies. And whereas not enough activity is associated with cancer, variants with enhanced activity are associated with degenerative diseases such as Alzheimer’s disease. This review describes the tightly controlled mechanisms that ensure PKC activity is perfectly balanced and what happens when these controls are deregulated. PKC isozymes serve as a paradigm for the wisdom of Confucius: “to go beyond is as wrong as to fall short.”

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“…Early studies showed that PKCδ overexpressing transgenic mice were resistant to certain types of chemically induced skin cancer (Reddig et al, 1999); however, these mice did get skin cancers with repeated exposure to UV irradiation (Aziz, Wheeler, Bhamb, & Verma, 2006). Similarly, Mischak et al showed that overexpression of PKCδ could suppress proliferation of NIH 3T3 cells (Mischak et al, 1993), and similar findings have been reported in a variety of cancer cells.…”

Section: Biological Functions Of Pkcδmentioning

confidence: 99%

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

Reyland

Jones

2016

Pharmacology & Therapeutics

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The serine–threonine protein kinase, protein kinase C-δ (PKCδ), is emerging as a bi-functional regulator of cell death and proliferation. Studies in PKCδ−/− mice have confirmed a pro-apoptotic role for this kinase in response to DNA damage and a tumor promoter role in some oncogenic contexts. In non-transformed cells, inhibition of PKCδ suppresses the release of cytochrome c and caspase activation, indicating a function upstream of apoptotic pathways. Data from PKCδ−/− mice demonstrate a role for PKCδ in the execution of DNA damage-induced and physiologic apoptosis. This has led to the important finding that inhibitors of PKCδ can be used therapeutically to reduce irradiation and chemotherapy-induced toxicity. By contrast, PKCδ is a tumor promoter in mouse models of mammary gland and lung cancer, and increased PKCδ expression is a negative prognostic indicator in Her2+ and other subtypes of human breast cancer. Understanding how these distinct functions of PKCδ are regulated is critical for the design of therapeutics to target this pathway. This review will discuss what is currently known about biological roles of PKCδ and prospects for targeting PKCδ in human disease.

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Protein Kinase C δ Overexpressing Transgenic Mice Are Resistant to Chemically but not to UV Radiation–Induced Development of Squamous Cell Carcinomas: A Possible Link to Specific Cytokines and Cyclooxygenase-2

Cited by 34 publications

References 45 publications

The Protein Kinase Cδ Catalytic Fragment Is Critical for Maintenance of the G2/M DNA Damage Checkpoint

The Protein Kinase Cδ Catalytic Fragment Is Critical for Maintenance of the G2/M DNA Damage Checkpoint

Protein kinase C: perfectly balanced

Multifunctional roles of PKCδ: Opportunities for targeted therapy in human disease

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