A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA

Komori, Keishi; Takagi, Yasuaki; Sanada, Masayuki; Lim, Teik How; Nakatsu, Yoshimichi; Tsuzuki, Teruhisa; Sekiguchi, Mutsuo; Hidaka, Masaaki

doi:10.1038/onc.2008.462

Cited by 11 publications

(14 citation statements)

References 38 publications

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“…FLCN forms a complex with FNIP1 and FNIP2 [11–13] to regulate multiple cellular processes, including energy sensing [14–16], differentiation [17], autophagy [18, 19], and apoptosis [20–23]. However, how this complex senses nutrient availability to control renal cancer tumorigenesis has remained elusive.…”

Section: Discussionmentioning

confidence: 99%

“…FLCN forms a complex with FLCN-interacting protein 1 (FNIP1) and FNIP2 [11–13] to regulate multiple cellular processes such as energy sensing [14–16], differentiation [17], autophagy [18, 19], and apoptosis [20–23]. Genetically engineered mouse models demonstrated that homozygous whole-body FNIP1 knockout mice displayed compromised B-cell development [23–25] and altered programming of muscle fiber-type switching [26].…”

Section: Introductionmentioning

confidence: 99%

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Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

et al. 2016

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Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dubé (BHD) syndrome, a rare disorder with increased risk of renal cancer. Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer. However, the molecular mechanism functionally linking FNIP1/FNIP2 and FLCN remains largely elusive. Here, we demonstrated that FNIP2 protein is unstable and subjected to proteasome-dependent degradation via β-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, which in turn promotes the proliferation of renal cancer cells. These results indicate that SCFβ-TRCP negatively regulates the FLCN complex by promoting FNIP degradation and provide molecular insight into the pathogenesis of BHD-associated renal cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

et al. 2016

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“…A second folliculin interacting protein, FNIP2, 67 also referred to as FNIPL 68 or MAPO1 69 , was identified by bioinformatics searches for FNIP1 homologous proteins. FNIP2 has 49% homology with FNIP1 and, like FNIP1, binds to the carboxy-terminus of FLCN and interacts with AMPK.…”

Section: Flcn Functional Studies and Interacting Proteinsmentioning

confidence: 99%

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

2015

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Birt-Hogg-Dubé (BHD) syndrome is an inherited renal cancer syndrome in which affected individuals are at risk to develop benign, cutaneous fibrofolliculomas, bilateral pulmonary cysts and spontaneous pneumothoraces, and kidney tumors. Bilateral multifocal renal tumors that develop in BHD syndrome are most frequently hybrid oncocytic tumors and chromophobe renal carcinoma, but may present with other histologies. Germline mutations in the FLCN gene on chromosome 17 are responsible for BHD syndrome. BHD-associated renal tumors show inactivation of the wild-type FLCN allele by somatic mutation or chromosomal loss, confirming that FLCN is a tumor suppressor gene that fits the classic two-hit model. FLCN interacts with two novel proteins, FNIP1 and FNIP2, and with AMPK, a negative regulator of mTOR. Studies with FLCN-deficient cell and animal models support a role for FLCN in modulating the AKT-mTOR pathway. Emerging evidence links FLCN with a number of other molecular pathways and cellular processes important for cell homeostasis that are frequently deregulated in cancer, including regulation of TFE3/TFEB transcriptional activity, amino acid-dependent mTOR activation through Rag GTPases, TGF-β signaling, PGC1α-driven mitochondrial biogenesis, and autophagy. Currently, surgical intervention is the only therapy available for BHD-associated renal tumors. Further understanding of the FLCN pathway will hopefully lead to the development of effective forms of therapy for this disease.

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“…Retrovirus-mediated gene-trap mutagenesis was performed to identify new genes functioning in the process of apoptosis triggered by O 6 -methylguanine, as described previously [22]. MNU-sensitive mouse-derived cells, due to the defect in MGMT activity, were infected with the gene-trap vector pLHΔU3L-Neo, carrying a promoterless hygromycin B resistance gene, and hygromycin-resistant cells were selected.…”

Section: Resultsmentioning

confidence: 99%

“…By using this method, we previously isolated a new gene, Mapo1 , which is involved in the O 6 -methylguanine-induced apoptosis [22]. The mouse cell line, KH101, carries a single insertion of the vector sequence in one of alleles of the Mapo1 gene, and is unable to induce apoptosis properly after treatment with MNU.…”

Section: Introductionmentioning

confidence: 99%

The Identification of a Novel Gene, MAPO2, That Is Involved in the Induction of Apoptosis Triggered by O6-Methylguanine

et al. 2012

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O6-Methylguanine, one of alkylated DNA bases, is especially mutagenic. Cells containing this lesion are eliminated by induction of apoptosis, associated with the function of mismatch repair (MMR) proteins. A retrovirus-mediated gene-trap mutagenesis was used to isolate new genes related to the induction of apoptosis, triggered by the treatment with an alkylating agent, N-methyl-N-nitrosourea (MNU). This report describes the identification of a novel gene, MAPO2 (O6-methylguanine-induced apoptosis 2), which is originally annotated as C1orf201. The MAPO2 gene is conserved among a wide variety of multicellular organisms and encodes a protein containing characteristic PxPxxY repeats. To elucidate the function of the gene product in the apoptosis pathway, a human cell line derived from HeLa MR cells, in which the MAPO2 gene was stably knocked down by expressing specific miRNA, was constructed. The knockdown cells grew at the same rate as HeLa MR, thus indicating that MAPO2 played no role in the cellular growth. After exposure to MNU, HeLa MR cells and the knockdown cells underwent cell cycle arrest at G2/M phase, however, the production of the sub-G1 population in the knockdown cells was significantly suppressed in comparison to that in HeLa MR cells. Moreover, the activation of BAK and caspase-3, and depolarization of mitochondrial membrane, hallmarks for the induction of apoptosis, were also suppressed in the knockdown cells. These results suggest that the MAPO2 gene product might positively contribute to the induction of apoptosis triggered by O6-methylguanine.

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A novel protein, MAPO1, that functions in apoptosis triggered by O6-methylguanine mispair in DNA

Cited by 11 publications

References 38 publications

Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

Molecular genetics and clinical features of Birt–Hogg–Dubé syndrome

The Identification of a Novel Gene, MAPO2, That Is Involved in the Induction of Apoptosis Triggered by O6-Methylguanine

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