MDM2 Is Required for Suppression of Apoptosis by Activated Akt1 in Salivary Acinar Cells

Limesand, Kirsten H.; Schwertfeger, Kathryn L.; Anderson, Steven M.

doi:10.1128/mcb.01846-05

Cited by 55 publications

(120 citation statements)

References 101 publications

(151 reference statements)

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“…87,88 Direct tissue damage may be related to p53-related apoptosis due to the development of reactive oxygen species leading to DNA damage and reduced insulin-like growth factor production. 89,90 RT has a dramatic effect on salivary function when the glands are within the RT field. The serous acini are initially more sensitive to RT.…”

Section: Rt-induced Xerostomia and Hyposalivationmentioning

confidence: 99%

Oral complications of cancer and cancer therapy

Epstein

Thariat

Bensadoun

et al. 2012

CA A Cancer J Clinicians

395

354

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Answer questions and earn CME/CNEOral complications resulting from cancer and cancer therapies cause acute and late toxicities that may be underreported, underrecognized, and undertreated. Recent advances in cancer treatment have led to changes in the incidence, nature, and severity of oral complications. As the number of survivors increases, it is becoming increasingly recognized that the aggressive management of oral toxicities is needed to ensure optimal long‐term oral health and general well‐being. Advances in care have had an impact on previously recognized oral complications and are leading to newly recognized adverse effects. Here, the authors briefly review advances in cancer therapy, including recent advances in surgery, oral care, radiation therapy, hematopoietic cell transplantation, and medical oncology; describe how these advances affect oral health; and discuss the frequent and/or severe oral health complications associated with cancer and cancer treatment and their effect upon long‐term health. Although some of the acute oral toxicities of cancer therapies may be reduced, they remain essentially unavoidable. The significant impact of long‐term complications requires increased awareness and recognition to promote prevention and appropriate intervention. It is therefore important for the primary oncologist to be aware of these complications so that appropriate measures can be implemented in a timely manner. Prevention and management is best provided via multidisciplinary health care teams, which must be integrated and communicate effectively in order to provide the best patient care in a coordinated manner at the appropriate time. CA Cancer J Clin 2012. © 2012 American Cancer Society.

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Section: Rt-induced Xerostomia and Hyposalivationmentioning

confidence: 99%

Oral complications of cancer and cancer therapy

Epstein

Thariat

Bensadoun

et al. 2012

CA A Cancer J Clinicians

395

354

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“…Primary acinar cells were isolated from the parotid glands of FVB mice and seeded onto collagen-coated plates, as previously described (Limesand et al 2006). After 4 d in culture, primary cells were starved overnight and irradiated.…”

Section: Primary Parotid Acinar Cell Isolation and Treatmentmentioning

confidence: 99%

Section: Immunoblotting and Immunoprecipitationmentioning

confidence: 99%

“…Membranes were probed with the following antibodies: histone H2A.X phosphorylated on serine (Ser)139 (Cell Signaling Technology), H2A (Cell Signaling Technology), extracellular signal-regulated kinase (ERK; Promega), replication protein A (RPA) phosphorylated on Ser4/8 (Bethyl Lab Inc.), Rad51 (Calbiochem), BRCA1 (Calbiochem), SirT-1 (H-300; Santa Cruz Biotechnology Inc.), SirT-2 (Cell Signaling Technology), SirT-3 (Cell Signaling Technology), Akt (Cell Signaling Technology). Membranes were stripped with Restore western blot stripping buffer (Thermo Fisher Scientific), reblocked, and reprobed, as previously described (Limesand et al 2006). Densitometry analysis was conducted using ImageJ software (NIH), as previously described .…”

Section: Immunoblotting and Immunoprecipitationmentioning

confidence: 99%

“…Glands were homogenized in radio immunoprecipitation assay (RIPA) buffer with protease and phosphatase inhibitors, as previously described (Limesand et al 2006). Samples were run on polyacrylamide gels and immunoblotted, as previously described (Limesand et al 2006). Membranes were probed with the following antibodies: histone H2A.X phosphorylated on serine (Ser)139 (Cell Signaling Technology), H2A (Cell Signaling Technology), extracellular signal-regulated kinase (ERK; Promega), replication protein A (RPA) phosphorylated on Ser4/8 (Bethyl Lab Inc.), Rad51 (Calbiochem), BRCA1 (Calbiochem), SirT-1 (H-300; Santa Cruz Biotechnology Inc.), SirT-2 (Cell Signaling Technology), SirT-3 (Cell Signaling Technology), Akt (Cell Signaling Technology).…”

Section: Immunoblotting and Immunoprecipitationmentioning

confidence: 99%

See 2 more Smart Citations

Insulin-Like Growth Factor-1–Mediated DNA Repair in Irradiated Salivary Glands Is Sirtuin-1 Dependent

et al. 2016

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Ionizing radiation is one of the most common cancer treatments; however, the treatment leads to a wide range of debilitating side effects. In patients with head and neck cancer (HNC), the surrounding normal salivary gland is extremely sensitive to therapeutic radiation, and damage to this tissue results in various oral complications and decreased quality of life (QOL). In the current study, mice treated with targeted head and neck radiation showed a significant increase in double-stranded breaks (DSB) in the DNA of parotid salivary gland cells immediately after treatment, and this remained elevated 3 h posttreatment. In contrast, mice pretreated with insulinlike growth factor-1 (IGF-1) showed resolution of the same amount of initial DNA damage by 3 h posttreatment. At acute time points (30 min to 2 h), irradiated parotid glands had significantly decreased levels of the histone deactylase Sirtuin-1 (SirT-1) which has been previously shown to function in DNA repair. Pretreatment with IGF-1 increased SirT-1 protein levels and increased deacetylation of SirT-1 targets involved in DNA repair. Pharmacological inhibition of SirT-1 activity decreased the IGF-1-mediated resolution of DSB. These data suggest that IGF-1 promotes DNA repair in irradiated parotid glands through the maintenance and activation of SirT-1.

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SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin‐like growth factor receptor pathway

Gagarina

Gabay

Dvir-Ginzberg

et al. 2010

Arthritis & Rheumatism

120

108

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Objective. The protein deacetylase SirT1 inhibits apoptosis in a variety of cell systems by distinct mechanisms, yet its role in chondrocyte death has not been explored. We undertook the present study to assess the role of SirT1 in the survival of osteoarthritic (OA) chondrocytes in humans.Methods. SirT1, protein tyrosine phosphatase 1B (PTP1B), and PTP1B mutant expression plasmids as well as SirT1 small interfering RNA (siRNA) and PTP1B siRNA were transfected into primary human chondrocytes. Levels of apoptosis were determined using flow cytometry, and activation of components of the insulin-like growth factor receptor (IGFR)/Akt pathway was assessed using immunoblotting. OA and normal knee cartilage samples were subjected to immunohistochemical analysis.Results. Expression of SirT1 in chondrocytes led to increased chondrocyte survival in either the presence or the absence of tumor necrosis factor ␣/actinomycin D, while a reduction of SirT1 by siRNA led to increased chondrocyte apoptosis. Expression of SirT1 in chondrocytes led to activation of IGFR and the downstream kinases phosphatidylinositol 3-kinase, phosphoinositedependent protein kinase 1, mTOR, and Akt, which in turn phosphorylated MDM2, inhibited p53, and blocked apoptosis. Activation of IGFR occurs at least in part via SirT1-mediated repression of PTP1B. Expression of PTP1B in chondrocytes increased apoptosis and reduced IGFR phosphorylation, while down-regulation of PTP1B by siRNA significantly decreased apoptosis. Examination of cartilage from normal donors and OA patients revealed that PTP1B levels are elevated in OA cartilage in which SirT1 levels are decreased.Conclusion. For the first time, it has been demonstrated that SirT1 is a mediator of human chondrocyte survival via down-regulation of PTP1B, a potent proapoptotic protein that is elevated in OA cartilage.

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MDM2 Is Required for Suppression of Apoptosis by Activated Akt1 in Salivary Acinar Cells

Cited by 55 publications

References 101 publications

Oral complications of cancer and cancer therapy

Oral complications of cancer and cancer therapy

Insulin-Like Growth Factor-1–Mediated DNA Repair in Irradiated Salivary Glands Is Sirtuin-1 Dependent

SirT1 enhances survival of human osteoarthritic chondrocytes by repressing protein tyrosine phosphatase 1B and activating the insulin‐like growth factor receptor pathway

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