Defining the DNA mismatch repair-dependent apoptotic pathway in primary cells: Evidence for p53-independence and involvement of centrosomal caspase 2

Narine, Kelly A.D.; Keuling, Angela M.; Gombos, Randi; Tron, Victor A.; Andrew, Susan E.; Young, Leah C.

doi:10.1016/j.dnarep.2009.11.010

Cited by 13 publications

(13 citation statements)

References 53 publications

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“…MMR deficiency is implicated in the development of apoptosis-resistance against wide range of DNA-damaging agents, including platinum drugs [195]. It is possible that MMR recognition of DNA damage may trigger an apoptotic pathway or that futile cycles of DNA damage/repair mediated by the mismatch repair machinery generate lethal DNA strand breaks [196]. MMR has a role beyond that of repair in response to DNA damage.…”

Section: Molecular Targeting Therapies and Apoptosismentioning

confidence: 99%

Apoptosis and Molecular Targeting Therapy in Cancer

Hassan

Watari

Abu-Almaaty

et al. 2014

BioMed Research International

943

720

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Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.

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Section: Molecular Targeting Therapies and Apoptosismentioning

confidence: 99%

Apoptosis and Molecular Targeting Therapy in Cancer

Hassan

Watari

Abu-Almaaty

et al. 2014

BioMed Research International

943

720

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“…However, also for the MMR, key player MSH2 functions in centrosome maintenance are reported [13]; Msh2 −/− mice showed an increased number of centrosomes in every third cell as well as modifications at the telomers. The localization of MSH2 at the centrosomes was reported subsequently by Narine et al , 2010 [14]. Furthermore, MMR family member MSH4 may be associated to centrosomes, as binding to the microtubule-synthesis associated protein VBP1 (von Hippel–Lindau binding protein 1) has been shown [15,16].…”

Section: Resultsmentioning

confidence: 89%

Localization of MLH3 at the Centrosomes

Roesner

Mielke

Faehnrich

et al. 2014

IJMS

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Mutations in human DNA mismatch repair (MMR) genes are commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC). MLH1 protein heterodimerizes with PMS2, PMS1, and MLH3 to form MutLα, MutLβ, and MutLγ, respectively. We reported recently stable expression of GFP-linked MLH3 in human cell lines. Monitoring these cell lines during the cell cycle using live cell imaging combined with confocal microscopy, we detected accumulation of MLH3 at the centrosomes. Fluorescence recovery after photobleaching (FRAP) revealed high mobility and fast exchange rates at the centrosomes as it has been reported for other DNA repair proteins. MLH3 may have a role in combination with other repair proteins in the control of centrosome numbers.

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“…MSH2 plays a key role in the recognition and repair of DNA replication errors, contributing to genomic integrity. In cancer cells, MSH2 identifies DNA adducts caused by many chemotherapeutic drugs and triggers further MMR-mediated signaling that results in cell cycle arrest and apoptosis (20, 21). In another report, we found that TGFβ downregulates ATM in BC cells by inducing the miR-181 family which targets the 3′UTR of ATM transcripts (19).…”

Section: Introductionmentioning

confidence: 99%

TGFβ Induces “BRCAness” and Sensitivity to PARP Inhibition in Breast Cancer by Regulating DNA-Repair Genes

Liu

Zhou

Cheng

et al. 2014

Molecular Cancer Research

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Transforming growth factor β (TGFβ) proteins are multitasking cytokines, whose high levels at tumor sites generally correlate with poor prognosis in human cancer patients. Previously it was reported that TGFβ downregulates the expression of ataxia telangiectasia mutated (ATM) and mutS homolog 2 (MSH2) in breast cancer (BC) cells through a miRNA-mediated mechanism. In this study, expression of a panel of DNA repair genes was examined, identifying breast cancer 1, early onset (BRCA1) as a target downregulated by TGFβ through the miR-181 family. Correlations between the expression levels of TGFβ1 and the miR-181/BRCA1 axis were observed in primary breast tumor specimens. By downregulating BRCA1, ATM, and MSH2, TGFβ orchestrates DNA damage response (DDR) in certain BC cells to induce a ‘BRCAness’ phenotype, including impaired DNA repair efficiency and synthetic lethality to the inhibition of poly (ADP-ribose) polymerase (PARP). Xenograft tumors with active TGFβ signaling exhibited resistance to the DNA-damaging agent doxorubicin but increased sensitivity to the PARP inhibitor ABT-888. Combination of doxorubicin with ABT-888 significantly improved the treatment efficacy in TGFβ-active tumors. Thus, TGFβ can induce ‘BRCAness’ in certain BCs carrying wild-type BRCA genes and enhance the responsiveness to PARP inhibition, and the molecular mechanism behind this is characterized. Implications: These findings enable better selection of sporadic breast cancer patients for PARP interventions, which have exhibited beneficial effects in patients carrying BRCA mutations.

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Defining the DNA mismatch repair-dependent apoptotic pathway in primary cells: Evidence for p53-independence and involvement of centrosomal caspase 2

Cited by 13 publications

References 53 publications

Apoptosis and Molecular Targeting Therapy in Cancer

Apoptosis and Molecular Targeting Therapy in Cancer

Localization of MLH3 at the Centrosomes

TGFβ Induces “BRCAness” and Sensitivity to PARP Inhibition in Breast Cancer by Regulating DNA-Repair Genes

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