Hypoxia signalling through mTOR and the unfolded protein response in cancer

Targeting HIF-1 for cancer therapy

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Signal integration in the endoplasmic reticulum unfolded protein response

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Upstream and downstream of mTOR

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Autophagy: process and functionPreprint

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The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation

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Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

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An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative Stress

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Defining the role of mTOR in cancer

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Exploiting tumour hypoxia in cancer treatment

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Molecular regulation of vessel maturation

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Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease

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Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours

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The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy

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Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis

Degenhardt, K., Mathew, R., Beaudoin, B., Bray, K., Anderson, D., Chen, G., Mukherjee, C., Shi, Y., Gélinas, C., Fan, Y., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.06.001 · Cited by 2,069

CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulumPreprint

Marciniak, S. J., Yun, C. Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H. P., & Ron, D. (2004) · Genes & Development · doi:10.1101/gad.1250704 · Cited by 2,066

CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulumPreprint

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Autophagy Is Activated for Cell Survival after Endoplasmic ReticulumStress

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Role of autophagy in cancer

Mathew, R., Karantza-Wadsworth, V., & White, E. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2254 · Cited by 1,798

Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells

Vattem, K. M., & Wek, R. C. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400541101 · Cited by 1,696

Untitled work

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Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex

Brugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., Witters, L. A., Ellisen, L. W., & Kaelin, W. G. (2004) · Genes & Development · doi:10.1101/gad.1256804 · Cited by 1,384

Translational Control Is Required for the Unfolded Protein Response and In Vivo Glucose Homeostasis

Scheuner, D. L., Song, B., McEwen, E. L., Liu, C., Laybutt, D. R., Gillespie, P. J., Saunders, T. L., Bonner‐Weir, S., & Kaufman, R. J. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00265-9 · Cited by 1,355

HER2 (neu) Signaling Increases the Rate of Hypoxia-Inducible Factor 1α (HIF-1α) Synthesis: Novel Mechanism for HIF-1-Mediated Vascular Endothelial Growth Factor Expression

Laughner, E., Taghavi, P., Chiles, K., Mahon, P. C., & Semenza, G. L. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.12.3995-4004.2001 · Cited by 1,256

Regulation of Hypoxia-Inducible Factor 1α Expression and Function by the Mammalian Target of Rapamycin

Hudson, C. C., Liu, M., Chiang, G. G., Otterness, D. M., Loomis, D. C., Kaper, F., Giaccia, A. J., & Abraham, R. T. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.20.7004-7014.2002 · Cited by 1,186

Functional and physical interaction between Bcl‐XL and a BH3‐like domain in Beclin‐1

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A MicroRNA Signature of Hypoxia

Kulshreshtha, R., Ferracin, M., Wojcik, S. E., Garzon, R., Alder, H., Agosto-Perez, F. J., Davuluri, R., Liu, C.-G., Croce, C. M., Negrini, M., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01395-06 · Cited by 1,055

Autophagy Counterbalances Endoplasmic Reticulum Expansion during the Unfolded Protein Response

Bernales, S., McDonald, K. L., & Walter, P. (2006) · PLoS Biology · doi:10.1371/journal.pbio.0040423 · Cited by 1,047

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Dewhirst, M. W., Cao, Y., & Moeller, B. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2397 · Cited by 1,022

Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response

Lu, P. D., Harding, H. P., & Ron, D. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200408003 · Cited by 1,006

Regulation of cap-dependent translation by eIF4E inhibitory proteins

Richter, J. D., & Sonenberg, N. (2005) · Nature · doi:10.1038/nature03205 · Cited by 972

ER stress (PERK/eIF2α phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation

Kouroku, Y., Fujita, E., Tanida, I., Ueno, T., Isoai, A., Kumagai, H., Ogawa, S., Kaufman, R. J., Kominami, E., & Momoi, T. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4401984 · Cited by 934

MicroRNA-210 Modulates Endothelial Cell Response to Hypoxia and Inhibits the Receptor Tyrosine Kinase Ligand Ephrin-A3

Fasanaro, P., D'Alessandra, Y., Di Stefano, V., Melchionna, R., Romani, S., Pompilio, G., Capogrossi, M. C., & Martelli, F. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800731200 · Cited by 912

HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity

Zhang, H., Gao, P., Fukuda, R., Kumar, G., Krishnamachary, B., Zeller, K. I., Dang, C. V., & Semenza, G. L. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.04.001 · Cited by 885

Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesisPreprint

Karantza‐Wadsworth, V., Patel, S. A., Kravchuk, O., Chen, G., Mathew, R., Jin, S., & White, E. (2007) · Genes & Development · doi:10.1101/gad.1565707 · Cited by 865

Loss of PTEN facilitates HIF-1-mediated gene expression

Zundel, W., Schindler, C., Haas-Kogan, D., Koong, A., Kaper, F., Chen, E., Gottschalk, A. R., Ryan, H. E., Johnson, R. S., Jefferson, A. B., et al. (2000) · Genes & Development · doi:10.1101/gad.14.4.391 · Cited by 840

HIF and c-Myc: Sibling Rivals for Control of Cancer Cell Metabolism and Proliferation

Gordan, J. D., Thompson, C. B., & Simon, M. C. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.07.006 · Cited by 819

Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium

Høyer-Hansen, M. H., & Jäättelä, M. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402200 · Cited by 785

HIF-2α Promotes Hypoxic Cell Proliferation by Enhancing c-Myc Transcriptional Activity

Gordan, J. D., Bertout, J. A., Hu, C.-J., Diehl, J. A., & Simon, M. C. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.02.006 · Cited by 781

ER stress‐regulated translation increases tolerance to extreme hypoxia and promotes tumor growth

Bi, M., Naczki, C., Koritzinsky, M., Fels, D. R., Blais, J. D., Hu, N., Harding, H. P., Novoa, I., Varia, M. A., Raleigh, J. A., et al. (2005) · The EMBO Journal · doi:10.1038/sj.emboj.7600777 · Cited by 756

The role of the unfolded protein response in tumour development: friend or foe?

Ma, Y., & Hendershot, L. M. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1505 · Cited by 712

Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2α

Koumenis, C., Naczki, C., Koritzinsky, M., Rastani, S., Diehl, J. A., Sonenberg, N., Koromilas, A. E., & Wouters, B. G. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.21.7405-7416.2002 · Cited by 711

Hypoxia regulates TSC1/2–mTOR signaling and tumor suppression through REDD1-mediated 14–3–3 shuttling

DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D., & Ellisen, L. W. (2008) · Genes & Development · doi:10.1101/gad.1617608 · Cited by 710

HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors.

Sowter, H., Ratcliffe, P. J., Watson, P. H., Greenberg, A. H., & Harris, A. L. (2001) · PubMed · Cited by 705

hsa-miR-210 Is Induced by Hypoxia and Is an Independent Prognostic Factor in Breast Cancer

Camps, C., Buffa, F. M., Colella, S., Moore, J., Sotiriou, C. P., Sheldon, H., Harris, A. L., Gleadle, J., & Ragoussis, J. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1755 · Cited by 672

Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway

Isaacs, J. S., Jung, Y.-J., Mimnaugh, E. G., Martinez, A., Cuttitta, F., & Neckers, L. M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204733200 · Cited by 663

MiRNA-Directed Regulation of VEGF and Other Angiogenic Factors under Hypoxia

Zhong, H., Lv, Q., Ye, W., Wong, C.-K. A., Cai, G., Gu, D., Ji, Y., Zhao, C., Wang, J., Yang, B. B., et al. (2006) · PLoS ONE · doi:10.1371/journal.pone.0000116 · Cited by 659

Protein quality control in the early secretory pathway

Anelli, T., & Sitia, R. (2008) · The EMBO Journal · doi:10.1038/sj.emboj.7601974 · Cited by 623

The interplay between MYC and HIF in cancer

Dang, C. V., Kim, J., Gao, P., & Yustein, J. T. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2274 · Cited by 621

Hypoxia-induced energy stress regulates mRNA translation and cell growth

Liu, L., Cash, T. P., Jones, R. G., Keith, B., Thompson, C. B., & Simon, M. C. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.010 · Cited by 607

Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer

Thomas, G. V., Tran, C., Mellinghoff, I. K., Welsbie, D. S., Chan, E., Fueger, B., Czernin, J., & Sawyers, C. L. (2006) · Nature Medicine · doi:10.1038/nm1337 · Cited by 604

XBP1 Is Essential for Survival under Hypoxic Conditions and Is Required for Tumor Growth

Romero‐Ramírez, L., Cao, H., Nelson, D. W., Hammond, E. M., Lee, A., Yoshida, H., Mori, K., Glimcher, L. H., Denko, N. C., Giaccia, A. J., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1606 · Cited by 587

Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis.

Huang, S., & Harari, P. M. (2000) · PubMed · Cited by 555

TSC2 regulates VEGF through mTOR-dependent and -independent pathways

Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R., & Kaelin, W. G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00187-9 · Cited by 528

Rapamycin-modulated transcription defines the subset of nutrient-sensitive signaling pathways directly controlled by the Tor proteins

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Hypoxia-inducible Factor 1α Is Regulated by the Mammalian Target of Rapamycin (mTOR) via an mTOR Signaling Motif

Land, S. C., & Tee, A. R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611782200 · Cited by 507

Translation of Vascular Endothelial Growth Factor mRNA by Internal Ribosome Entry: Implications for Translation under Hypoxia

Stein, I., Itin, A., Einat, P., Skaliter, R., Grossman, Z., & Keshet, E. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.6.3112 · Cited by 507

Induction of Vascular Endothelial Growth Factor by Hypoxia Is Modulated by a Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Ha-ras-Transformed Cells Through a Hypoxia Inducible Factor-1 Transcriptional Element

Mazure, N. M., Chen, E. Y., Laderoute, K. R., & Giaccia, A. J. (1997) · Blood · doi:10.1182/blood.v90.9.3322 · Cited by 500

A Novel Hypoxia-inducible Factor-independent Hypoxic Response Regulating Mammalian Target of Rapamycin and Its Targets

Arsham, A. M., Howell, J. J., & Simon, M. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212770200 · Cited by 463

Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress

Blais, J. D., Filippenko, V., Bi, M., Harding, H. P., Ron, D., Koumenis, C., Wouters, B. G., & Bell, J. C. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.17.7469-7482.2004 · Cited by 459

Delineation of a Negative Feedback Regulatory Loop That Controls Protein Translation during Endoplasmic Reticulum Stress

Ma, Y., & Hendershot, L. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301107200 · Cited by 458

Loss of the Tuberous Sclerosis Complex Tumor Suppressors Triggers the Unfolded Protein Response to Regulate Insulin Signaling and Apoptosis

Özcan, U., Özcan, L., Yılmaz, E., Düvel, K., Şahin, M., Manning, B. D., & Hotamışlıgil, G. S. (2008) · Molecular Cell · doi:10.1016/j.molcel.2007.12.023 · Cited by 449

Regulation of mTOR and Cell Growth in Response to Energy Stress by REDD1

Sofer, A., Lei, K., Johannessen, C. M., & Ellisen, L. W. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.14.5834-5845.2005 · Cited by 449

The FAD- and O2-Dependent Reaction Cycle of Ero1-Mediated Oxidative Protein Folding in the Endoplasmic Reticulum

Tu, B. P., & Weissman, J. S. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00696-2 · Cited by 433

Autophagy in chronically ischemic myocardium

Yan, L., Vatner, D. E., Kim, S.-J., Ge, H., Masurekar, M., Massover, W. H., Yang, G., Matsui, Y., Sadoshima, J., & Vatner, S. F. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506843102 · Cited by 430

The Immunosuppressant Rapamycin Mimics a Starvation-Like Signal Distinct from Amino Acid and Glucose Deprivation

Peng, T., Golub, T. R., & Sabatini, D. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5575-5584.2002 · Cited by 404

Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance

Erler, J. T., Cawthorne, C. J., Williams, K. J., Koritzinsky, M., Wouters, B. G., Wilson, C., Miller, C., Demonacos, C., Stratford, I. J., & Dive, C. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.7.2875-2889.2004 · Cited by 400

PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR

Bernardi, R., Guernah, I., Jin, D. K., Grisendi, S., Alimonti, A., Teruya‐Feldstein, J., Cordon‐Cardo, C., Simon, M. C., Rafii, S., & Pandolfi, P. P. (2006) · Nature · doi:10.1038/nature05029 · Cited by 379

Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control

Koritzinsky, M., Magagnin, M. G., van den Beucken, T., Seigneuric, R., Savelkouls, K. G. M., Dostie, J., Pyronnet, S., Kaufman, R. J., Weppler, S. A., Voncken, J. W., et al. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7600998 · Cited by 369

SR 4233 (Tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours

Brown, J. M. (1993) · British Journal of Cancer · doi:10.1038/bjc.1993.220 · Cited by 367

Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3

Azad, M. B., Chen, Y., Henson, E. S., Cizeau, J., McMillan‐Ward, E., Israels, S. J., & Gibson, S. B. (2008) · Autophagy · doi:10.4161/auto.5278 · Cited by 355

Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway

Denoyelle, C., Abou-Rjaily, G., Bezrookove, V., Verhaegen, M., Johnson, T. M., Fullen, D. R., Pointer, J. N., Gruber, S. B., Su, L. D., Nikiforov, M. A., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1471 · Cited by 349

miR-210 links hypoxia with cell cycle regulation and is deleted in human epithelial ovarian cancer

Giannakakis, A., Sandaltzopoulos, R., Greshock, J. D., Liang, S., Huang, J., Hasegawa, K., Li, C., O’Brien-Jenkins, A., Katsaros, D., Weber, B. L., et al. (2008) · Cancer Biology & Therapy · doi:10.4161/cbt.7.2.5297 · Cited by 348

Hypoxia signals autophagy in tumor cells via AMPK activity, independent of HIF-1, BNIP3, and BNIP3L

Papandreou, I., Lim, A. L., Laderoute, K., & Denko, N. C. (2008) · Cell Death & Differentiation · doi:10.1038/cdd.2008.84 · Cited by 334

Cerebral Ischemia-Hypoxia Induces Intravascular Coagulation and Autophagy

Adhami, F., Liao, G., Morozov, Y. M., Schloemer, A., Schmithorst, V. J., Lorenz, J. N., Dunn, R. S., Vorhees, C. V., Wills-Karp, M., Degen, J. L., et al. (2006) · The American Journal of Pathology · doi:10.2353/ajpath.2006.051066 · Cited by 326

Nelfinavir, A Lead HIV Protease Inhibitor, Is a Broad-Spectrum, Anticancer Agent that Induces Endoplasmic Reticulum Stress, Autophagy, and Apoptosis In vitro and In vivo

Gills, J. J., LoPiccolo, J., Tsurutani, J., Shoemaker, R. H., Best, C. J. M., Abu-Asab, M. S., Borojerdi, J. P., Warfel, N. A., Gardner, E. R., Danish, M., et al. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-0161 · Cited by 322

A hypoxia-controlled cap-dependent to cap-independent translation switch in breast cancer.

Braunstein, S., Karpisheva, K., Pola, C., Goldberg, J., Hochman, T., Yee, H., Cangiarella, J., Arju, R., Formenti, S., & Schneider, R. (2007) · Molecules and Cells · doi:10.1016/j.molcel.2007.10.019 · Cited by 320

Antiangiogenic Potential of the Mammalian Target of Rapamycin Inhibitor Temsirolimus

Bufalo, D. D., Ciuffreda, L., Trisciuoglio, D., Desideri, M., Cognetti, F., Zupi, G., & Milella, M. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2825 · Cited by 318

Hypoxia-inducible Factor-1α mRNA Contains an Internal Ribosome Entry Site That Allows Efficient Translation during Normoxia and Hypoxia

Lang, K. J. D., Kappel, A., & Goodall, G. J. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.02-02-0017 · Cited by 314

Perk-Dependent Translational Regulation Promotes Tumor Cell Adaptation and Angiogenesis in Response to Hypoxic Stress

Blais, J. D., Addison, C., Edge, R. E., Falls, T. J., Zhao, H., Wary, K. K., Koumenis, C., Harding, H. P., Ron, D., Holčı́k, M., et al. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01145-06 · Cited by 313

The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in DrosophilaPreprint

Reiling, J. H., & Hafen, E. (2004) · Genes & Development · doi:10.1101/gad.322704 · Cited by 306

Geldanamycin induces degradation of hypoxia-inducible factor 1alpha protein via the proteosome pathway in prostate cancer cells.

Mabjeesh, N. J., Post, D. E., Willard, M. T., Kaur, B., Meir, E. G. V., Simons, J. W., & Zhong, H. (2002) · PubMed · Cited by 299

ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase

平田, 晃. (2004) · Medical Entomology and Zoology · Cited by 296

Bortezomib Mediates Antiangiogenesis in Multiple Myeloma via Direct and Indirect Effects on Endothelial Cells

Roccaro, A. M., Hideshima, T., Raje, N. S., Kumar, S. K., Ishitsuka, K., Yasui, H., Shiraishi, N., Ribatti, D., Nico, B., Vacca, A., et al. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-1195 · Cited by 283

High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma

HEBERT, C. A., Norris, K., Scheper, M. A., Nikitakis, N. G., & Sauk, J. J. (2007) · Molecular Cancer · doi:10.1186/1476-4598-6-5 · Cited by 278

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Li, Y., Wang, Y., Kim, E., Beemiller, P., Wang, C. Y., Swanson, J. A., You, M., & Guan, K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m705231200 · Cited by 269

Up-regulation of Protein-disulfide Isomerase in Response to Hypoxia/Brain Ischemia and Its Protective Effect against Apoptotic Cell Death

Tanaka, S., Uehara, T., & Nomura, Y. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.14.10388 · Cited by 267

A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay

Ferraiuolo, M. A., Basak, S., Dostie, J., Murray, E. L., Schoenberg, D. R., & Sonenberg, N. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200504039 · Cited by 267

ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase.

Hirata, A., Ogawa, S.-I., Kometani, T., Kuwano, T., Naito, S., Kuwano, M., & Ono, M. (2002) · PubMed · Cited by 258

A Novel mTOR-Regulated Phosphorylation Site in Elongation Factor 2 Kinase Modulates the Activity of the Kinase and Its Binding to Calmodulin

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