Stat3 controls lysosomal-mediated cell death in vivo
Open accessAbstract
It is well established that lysosomes play an active role during the execution of cell death. A range of stimuli can lead to lysosomal membrane permeabilization (LMP), thus inducing programmed cell death without involvement of the classical apoptotic programme. However, these lysosomal pathways of cell death have mostly been described in vitro or under pathological conditions. Here we show that the physiological process of post-lactational regression of the mammary gland is accomplished through a non-classical, lysosomal-mediated pathway of cell death. We found that, during involution, lysosomes in the mammary epithelium undergo widespread LMP. Furthermore, although cell death through LMP is independent of executioner caspases 3, 6 and 7, it requires Stat3, which upregulates the expression of lysosomal proteases cathepsin B and L, while downregulating their endogenous inhibitor Spi2A (ref. 8). Our findings report a previously unknown, Stat3-regulated lysosomal-mediated pathway of cell death under physiological circumstances. We anticipate that these findings will be of major importance in the design of treatments for cancers such as breast, colon and liver, where cathepsins and Stat3 are commonly overexpressed and/or hyperactivated respectively.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
STAT3 promotes lysosome-dependent cell death during mammary gland involution post-lactation by upregulating CTSB and CTSL and downregulating SPI2A.
“Moreover, STAT3 reportedly promotes lysosome-dependent cell death during the involution of mammary gland post-lactation as it upregulates the expression of cathepsin B (CTSB) and CTSL, while downregulating their endogenous inhibitor serine (or cysteine) peptidase inhibitor, clade A, member 3G (SERPINA3G; best known as SPI2A) [774, 775].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [774]
Cites
STATs in cancer inflammation and immunity: a leading role for STAT3
Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383 · see citing works
Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G.-Y., Vallabhapurapu, S., Scheller, J., Rose-John, S., Cheroutre, H., Eckmann, L., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.01.001 · Cited by 2,155 · see citing works
Holler, N., Zaru, R., Micheau, O., Thome, M., Attinger, A., Valitutti, S., Bodmer, J.-L., Schneider, P., Seed, B., & Tschopp, J. (2000) · Nature Immunology · doi:10.1038/82732 · Cited by 1,932 · see citing works
Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice
Kuida, K., Zheng, T. S., Na, S., Kuan, C.-Y., Yang, D., Karasuyama, H., RAKIC, P. T., & Flavell, R. A. (1996) · Nature · doi:10.1038/384368a0 · Cited by 1,881 · see citing works
Self-citationLysosomes and autophagy in cell death control
Kroemer, G., & Jäättelä, M. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1738 · Cited by 1,291 · see citing works
multifunctional enzymes in cancer
Mohamed, M. M., & Sloane, B. F. (2006) · Nature reviews. Cancer · doi:10.1038/nrc1949 · Cited by 1,267 · see citing works
Caspases 3 and 7: Key Mediators of Mitochondrial Events of Apoptosis
Lakhani, S. A., Masud, A. J., Kuida, K., Porter, G. A., Jr., Booth, C. J., Mehal, W. Z., Inayat, I., & Flavell, R. A. (2006) · Science · doi:10.1126/science.1115035 · Cited by 1,175 · see citing works
Self-citationHitomi, J., Christofferson, D. E., Ng, A., Yao, J., Degterev, A., Xavier, R. J., & Yuan, J. (2008) · Cell · doi:10.1016/j.cell.2008.10.044 · Cited by 989 · see citing works
Lactation : a comprehensive treatise
Larson, B. L., & Smith, V. R. (1974) · Medical Entomology and Zoology · Cited by 749 · see citing works
A Nonapoptotic Cell Death Process, Entosis, that Occurs by Cell-in-Cell Invasion
Overholtzer, M., Mailleux, A. A., Mouneimne, G., Normand, G., Schnitt, S. J., King, R. W., Cibas, E. S., & Brugge, J. S. (2007) · Cell · doi:10.1016/j.cell.2007.10.040 · Cited by 748 · see citing works
Guicciardi, M. E., Leist, M., & Gores, G. J. (2004) · Oncogene · doi:10.1038/sj.onc.1207512 · Cited by 716 · see citing works
Foghsgaard, L., Wissing, D., Mauch, D., Lademann, U. A., Bastholm, L., Boes, M. L., Elling, F., Leist, M., & Jäättelä, M. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.5.999 · Cited by 629 · see citing works
Lund, L. R., Rømer, J., Thomasset, N., Solberg, H., Pyke, C., Bissell, M. J., Danø, K., & Werb, Z. (1996) · Development · doi:10.1242/dev.122.1.181 · Cited by 547 · see citing works
Chapman, R. S., Lourenco, P. C., Tonner, E., Flint, D. J., Selbert, S., Takeda, K., Akira, S., Clarke, A. R., & Watson, C. J. (1999) · Genes & Development · doi:10.1101/gad.13.19.2604 · Cited by 480 · see citing works
Self-citationSphingosine-induced apoptosis is dependent on lysosomal proteases
Kågedal, K., Ming, Z. H. A. O., Svensson, I., & Brunk, U. T. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3590335 · Cited by 379 · see citing works
Yamashima, T. (2000) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00006-x · Cited by 349 · see citing works
Clarkson, R. W. E., Wayland, M. T., Lee, J., Freeman, T. C., & Watson, C. J. (2003) · Breast Cancer Research · doi:10.1186/bcr754 · Cited by 329 · see citing works
Self-citationAlonzi, T., Maritano, D., Gorgoni, B., Rizzuto, G., Libert, C., & Poli, V. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.5.1621-1632.2001 · Cited by 329 · see citing works
Self-citationDeficiency in caspase-9 or caspase-3 induces compensatory caspase activation
Zheng, T. S., Hunot, S., Kuida, K., Momoi, T., Srinivasan, A. N., Nicholson, D. W., Lazebnik, Y. A., & Flavell, R. A. (2000) · Nature Medicine · doi:10.1038/81343 · Cited by 310 · see citing works
Self-citationSphingosine-induced apoptosis is dependent on lysosomal proteases
Kågedal, K., Ming, Z. H. A. O., Svensson, I., et al. (2001) · Biochemical Journal · doi:10.1042/bj3590335 · Cited by 273 · see citing works
Caspase-independent cell death?
Lockshin, R. A., & Zakeri, Z. F. (2004) · Oncogene · doi:10.1038/sj.onc.1207514 · Cited by 270 · see citing works
YU, Z., ZHANG, W., & KONE, B. C. (2002) · Biochemical Journal · doi:10.1042/bj20020588 · Cited by 255 · see citing works
Fehrenbacher, N., Bastholm, L., Kirkegaard‐Sørensen, T., Rafn, B., Bøttzauw, T., Nielsen, C. W., Weber, E., Shirasawa, S., Kallunki, T., & Jäättelä, M. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0463 · Cited by 242 · see citing works
Zhou, Q., Krebs, J., Snipas, S. J., Price, A., Alnemri, E. S., Tomaselli, K. J., & Salvesen, G. S. (1998) · Biochemistry · doi:10.1021/bi980893w · Cited by 216 · see citing works
Guicciardi, M. E., Miyoshi, H., Bronk, S. F., & Gores, G. J. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63056-8 · Cited by 204 · see citing works
Kritikou, E. A., Sharkey, A., Abell, K., Came, P. J., Anderson, E. L., Clarkson, R. W. E., & Watson, C. J. (2003) · Development · doi:10.1242/dev.00578 · Cited by 201 · see citing works
Self-citationTransforming growth factor β3 induces cell death during the first stage of mammary gland involution
Nguyen, A., & Pollard, J. W. (2000) · Development · doi:10.1242/dev.127.14.3107 · Cited by 179 · see citing works
Multiple Pathways of TWEAK-Induced Cell Death
NAKAYAMA, M., Ishidoh, K., Kayagaki, N., Kojima, Y., Yamaguchi, N., Nakano, H., Kominami, E., Okumura, K., & Yagita∥, H. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.2.734 · Cited by 167 · see citing works
Luke, C. J., Pak, S. C., Askew, Y. S., Naviglia, T. L., Askew, D. J., Nobar, S. M., Vetica, A. C., Long, O. S., Watkins, S. C., Stolz, D. B., et al. (2007) · Cell · doi:10.1016/j.cell.2007.07.013 · Cited by 166 · see citing works
Eradication of glioblastoma, and breast and colon carcinoma xenografts by Hsp70 depletion.
Nylandsted, J., Wick, W., Hirt, U. A., Brand, K., Rohde, M., Leist, M., Weller, M., & Jäättelä, M. (2002) · PubMed · Cited by 141 · see citing works
The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development
Khaled, W. T., Read, E. K. C., Nicholson, S. E., Baxter, F. O., Brennan, A. J., Came, P. J., Sprigg, N. S., McKenzie, A. N. J., & Watson, C. J. (2007) · Development · doi:10.1242/dev.003194 · Cited by 133 · see citing works
Self-citationNF‐κB protects from the lysosomal pathway of cell death
Liu, N., Raja, S. M., Zazzeroni, F., Metkar, S. S., Shah, R., Zhang, M., Wang, Y., Brömme, D., Russin, W. A., Lee, J. C., et al. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg510 · Cited by 116 · see citing works
Vasiljeva, O. S., Korovin, M. S., Gajda, M. R., Brodoefel, H., Bojić, L., Krüger, A., Schurigt, U., Sevenich, L., Turk, B., Peters, C., et al. (2008) · Oncogene · doi:10.1038/onc.2008.59 · Cited by 115 · see citing works
NF-κB Inhibits Apoptosis in Murine Mammary Epithelia
Clarkson, R. W. E., Heeley, J. L., Chapman, R. S., Aillet, F., Hay, R. T., Wyllie, A. H., & Watson, C. J. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.17.12737 · Cited by 112 · see citing works
Self-citationEfficient BLG-Cre Mediated Gene Deletion in the Mammary Gland
Selbert, S., & Bentley, D. J. (1998) · Transgenic Research · doi:10.1023/a:1008848304391 · Cited by 99 · see citing works
C/EBPδ is a crucial regulator of pro-apoptotic gene expression during mammary gland involution
Thangaraju, M., Rudelius, M., Bierie, B., Raffeld, M. A., Sharan, S., Hennighausen, L. G., Huang, A., & Sterneck, E. (2005) · Development · doi:10.1242/dev.02050 · Cited by 99 · see citing works
IKKβ/2 induces TWEAK and apoptosis in mammary epithelial cells
Baxter, F. O., Came, P. J., Abell, K., Kedjouar, B., Huth, M., Rajewsky, K., Pasparakis, M., & Watson, C. J. (2006) · Development · doi:10.1242/dev.02502 · Cited by 96 · see citing works
Self-citationSerine protease inhibitor 2A is a protective factor for memory T cell development
Liu, N., Phillips, T., Zhang, M., Wang, Y., Opferman, J. T., Shah, R., & Ashton‐Rickardt, P. G. (2004) · Nature Immunology · doi:10.1038/ni1107 · Cited by 86 · see citing works
Tiffen, P. G., Omidvar, N., Almuina, N. M., Croston, D., Watson, C. J., & Clarkson, R. W. E. (2008) · Molecular Endocrinology · doi:10.1210/me.2008-0097 · Cited by 74 · see citing works
Self-citationThe Beginning of the End: Death Signaling in Early Involution
Baxter, F. O., Neoh, K., & Tevendale, M. (2007) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-007-9033-9 · Cited by 67 · see citing works
Mammary gland involution is associated with rapid down regulation of major mammary Ca2+-ATPases
Reinhardt, T. A., & Lippolis, J. D. (2008) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2008.11.004 · Cited by 66 · see citing works
Warley, A., Powell, J. M., & Skepper, J. N. (1995) · Diabetologia · doi:10.1007/bf00410278 · Cited by 55 · see citing works
Inglis, J. D., & Hill, R. E. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb07945.x · Cited by 49 · see citing works
Mouse mammary gland involution is associated with cytochrome c release and caspase activation
Marti, A., Ritter, P. M., Jäger, R., Lazar, H., Baltzer, A., Schenkel, J., Declercq, W., Vandenabeele, P., & Jaggi, R. B. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(01)00381-1 · Cited by 38 · see citing works
Zaragozá, R., Torres, L., Garcı́a, C., Eroles, P., Corrales, F. J., Bosch, A., Lluch, A. M., García–Trevijano, E. R., & Vinã, J. R. (2009) · Biochemical Journal · doi:10.1042/bj20081746 · Cited by 32 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
The molecular machinery of regulated cell death
Tang, D., Kang, R., Berghe, T. V., Vandenabeele, P., & Kroemer, G. (2019) · Cell Research · doi:10.1038/s41422-019-0164-5 · Cited by 2,595 · see citing works
Regulated necrosis: the expanding network of non-apoptotic cell death pathways
Berghe, T. V., Linkermann, A., Jouan-Lanhouet, S., Walczak, H., & Vandenabeele, P. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3737 · Cited by 1,735 · see citing works
Lysosomes as dynamic regulators of cell and organismal homeostasis
Ballabio, A., & Bonifacino, J. S. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0185-4 · Cited by 1,469 · see citing works
Caspase‐1‐induced pyroptotic cell death
Miao, E. A., Rajan, J. V., & Aderem, A. A. (2011) · Immunological Reviews · doi:10.1111/j.1600-065x.2011.01044.x · Cited by 1,139 · see citing works
Macias, H., & Hinck, L. (2012) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.35 · Cited by 854 · see citing works
Lysosomal membrane permeabilization and cell death
Wang, F., Gómez‐Sintes, R., & Boya, P. (2018) · Traffic · doi:10.1111/tra.12613 · Cited by 781 · see citing works
The lysosome: from waste bag to potential therapeutic target
Appelqvist, H., Wäster, P., Kågedal, K., & Öllinger, K. (2013) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjt022 · Cited by 772 · see citing works
Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response
Olson, O. C., & Joyce, J. A. (2015) · Nature reviews. Cancer · doi:10.1038/nrc4027 · Cited by 703 · see citing works
Lysosomal cell death at a glance
Aits, S., & Jäättelä, M. (2013) · Journal of Cell Science · doi:10.1242/jcs.091181 · Cited by 667 · see citing works
The role of STAT3 in autophagy
You, L., Wang, Z., Li, H., Shou, J., Jing, Z., Xie, J., Sui, X., Pan, H., & Han, W. (2015) · Autophagy · doi:10.1080/15548627.2015.1017192 · Cited by 515 · see citing works
Eckhart, L., Lippens, S., Tschachler, E., & Declercq, W. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.010 · Cited by 515 · see citing works
Therapeutically exploiting STAT3 activity in cancer — using tissue repair as a road map
Huynh, J., Chand, A. L., Gough, D. J., & Ernst, M. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0090-8 · Cited by 507 · see citing works
Lysosome biogenesis: Regulation and functions
Yang, C., & Wang, X.-C. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202102001 · Cited by 420 · see citing works
Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification
Li, D. ‘., Wang, Z. V., Ding, G., Tan, W. H., Luo, X., Criollo, A., Xie, M., Jiang, N., May, H. I., Kyrychenko, V., et al. (2016) · Circulation · doi:10.1161/circulationaha.115.017443 · Cited by 466 · see citing works
Sensitive detection of lysosomal membrane permeabilization by lysosomal galectin puncta assay
Aits, S., Kricker, J. A., Liu, B., Ellegaard, A., Hämälistö, S., Tvingsholm, S. A., Corcelle–Termeau, E., Høgh, S., Farkas, T., Jonassen, A. H., et al. (2015) · Autophagy · doi:10.1080/15548627.2015.1063871 · Cited by 439 · see citing works
Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment
Vidak, E., Javoršek, U., Vizovišek, M., & Turk, B. (2019) · Cells · doi:10.3390/cells8030264 · Cited by 365 · see citing works
Petersen, N. H. T., Olsen, O. D., Groth‐Pedersen, L., Ellegaard, A., Bilgin, M., Redmer, S., Ostenfeld, M. S., Ulanet, D., Dovmark, T. H., Lønborg, A., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.08.003 · Cited by 335 · see citing works
The Multifaced Role of STAT3 in Cancer and Its Implication for Anticancer Therapy
Tolomeo, M., & Cascio, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020603 · Cited by 323 · see citing works
Feng, Y., Yao, Z., & Klionsky, D. J. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.02.002 · Cited by 319 · see citing works
Dorayappan, K. D. P., Wanner, R. A., Wallbillich, J. J., Saini, U., Zingarelli, R. A., Suarez, A. A., Cohn, D. E., & Selvendiran, K. (2018) · Oncogene · doi:10.1038/s41388-018-0189-0 · Cited by 309 · see citing works
Regulation of autophagy by stress-responsive transcription factors
Pietrocola, F., Izzo, V., Niso‐Santano, M., Vacchelli, E., Galluzzi, L., Maiuri, M. C., & Kroemer, G. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.05.008 · Cited by 270 · see citing works
Emerging roles for lipids in non-apoptotic cell death
Magtanong, L., Ko, P., & Dixon, S. J. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2016.25 · Cited by 259 · see citing works
Anatomy of the human mammary gland: Current status of knowledge
Hassiotou, F., & Geddes, D. T. (2012) · Clinical Anatomy · doi:10.1002/ca.22165 · Cited by 260 · see citing works
STAT1 and STAT3 in tumorigenesis
Avalle, L., Pensa, S., Regis, G., Novelli, F., & Poli, V. (2012) · JAK-STAT · doi:10.4161/jkst.20045 · Cited by 255 · see citing works
Self-citationFerroptosis is a lysosomal cell death process
Gao, H., Bai, Y., Jia, Y., Zhao, Y., Kang, R., Tang, D., & Dai, E. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.07.078 · Cited by 249 · see citing works
Organelle-specific initiation of cell death
Galluzzi, L., Bravo-San Pedro, J. M., & Kroemer, G. (2014) · Nature Cell Biology · doi:10.1038/ncb3005 · Cited by 239 · see citing works
Lysosomal cell death mechanisms in aging
Gómez-Sintes, R., Ledesma, M. D., & Boya, P. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.02.009 · Cited by 216 · see citing works
Lysosomal Function and Dysfunction: Mechanism and Disease
Boya, P. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4405 · Cited by 211 · see citing works
Serrano‐Puebla, A., & Boya, P. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12966 · Cited by 204 · see citing works
Cysteine cathepsins in extracellular matrix remodeling: Extracellular matrix degradation and beyond
Vizovišek, M., Fonović, M., & Turk, B. (2019) · Matrix Biology · doi:10.1016/j.matbio.2018.01.024 · Cited by 200 · see citing works
Sarkar, C., Jones, J. W., Hegdekar, N., Thayer, J. A., Kumar, A., Faden, A. I., Kane, M. A., & Lipinski, M. M. (2019) · Autophagy · doi:10.1080/15548627.2019.1628538 · Cited by 188 · see citing works
Sargeant, T. J., Lloyd-Lewis, B., Resemann, H. K., Ramos-Montoya, A., Skepper, J., & Watson, C. J. (2014) · Nature Cell Biology · doi:10.1038/ncb3043 · Cited by 168 · see citing works
Self-citationRemodeling mechanisms of the mammary gland during involution
Watson, C. J., & Kreuzaler, P. A. (2011) · The International Journal of Developmental Biology · doi:10.1387/ijdb.113414cw · Cited by 166 · see citing works
Self-citationO’Brien, J., Martinson, H. A., Durand‐Rougely, C., & Schedin, P. S. (2011) · Development · doi:10.1242/dev.071696 · Cited by 163 · see citing works
Sosna, J., Voigt, S., Mathieu, S., Lange, A., Thon, L., Davarnia, P., Herdegen, T., Linkermann, A., Rittger, A., Chan, F. K.-M., et al. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1381-6 · Cited by 162 · see citing works
Killing a cancer: what are the alternatives?
Kreuzaler, P. A., & Watson, C. J. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3264 · Cited by 162 · see citing works
Self-citationEfferocytosis produces a prometastatic landscape during postpartum mammary gland involution
Stanford, J. C., Young, C. D., Hicks, D. J., Owens, P., Williams, A., Vaught, D., Morrison, M. M., Lim, J., Williams, M. M., Brantley‐Sieders, D. M., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci76375 · Cited by 160 · see citing works
Lysosomal membrane permeabilization as a cell death mechanism in cancer cells
Serrano‐Puebla, A., & Boya, P. (2018) · Biochemical Society Transactions · doi:10.1042/bst20170130 · Cited by 148 · see citing works
Coburn, C., Allman, E. L., Mahanti, P., Benedetto, A., Cabreiro, F., Pincus, Z., Matthijssens, F., Araiz, C., Mandel, A., Vlachos, M., et al. (2013) · PLoS Biology · doi:10.1371/journal.pbio.1001613 · Cited by 143 · see citing works
Activation of Asparaginyl Endopeptidase Leads to Tau Hyperphosphorylation in Alzheimer Disease
Basurto‐Islas, G., Grundke, I., Tung, Y. C., Liu, F., & Iqbal, K. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.446070 · Cited by 141 · see citing works
Rodríguez‐Muela, N., Hernández‐Pinto, A. M., Serrano‐Puebla, A., García‐Ledo, L., Latorre, S., de la Rosa, E. J., & Boya, P. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.203 · Cited by 140 · see citing works
How Lysosomes Sense, Integrate, and Cope with Stress
Säftig, P., & Puertollano, R. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.09.004 · Cited by 135 · see citing works
The Endolysosomal System in Cell Death and SurvivalPreprint
Repnik, U., Česen, M. H., & Turk, B. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008755 · Cited by 137 · see citing works
Cell Death Pathways: a Novel Therapeutic Approach for Neuroscientists
Morris, G., Walker, A. J., Berk, M., Maes, M. H. J., & Puri, B. K. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0793-y · Cited by 129 · see citing works
Mechanisms of Regulated Cell Death: Current Perspectives
Santagostino, S. F., Assenmacher, C., Tarrant, J. C., Adedeji, A. O., & Radaelli, E. (2021) · Veterinary Pathology · doi:10.1177/03009858211005537 · Cited by 133 · see citing works
STAT signaling in mammary gland differentiation, cell survival and tumorigenesis
Haricharan, S., & Li, Y. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.03.014 · Cited by 130 · see citing works
Hughes, K., Wickenden, J. A., Allen, J. E., & Watson, C. J. (2011) · The Journal of Pathology · doi:10.1002/path.3961 · Cited by 125 · see citing works
Self-citationReproductive history and breast cancer risk
Kobayashi, S., Sugiura, H., Ando, Y., Shiraki, N., Yanagi, T., Yamashita, H., & Toyama, T. (2012) · Breast Cancer · doi:10.1007/s12282-012-0384-8 · Cited by 123 · see citing works
LAMP3 inhibits autophagy and contributes to cell death by lysosomal membrane permeabilization
Tanaka, T., Warner, B. M., Michael, D. G., Nakamura, H., Odani, T., Yin, H., Atsumi, T., Noguchi, M., & Chiorini, J. A. (2021) · Autophagy · doi:10.1080/15548627.2021.1995150 · Cited by 122 · see citing works
Lysosomal proteins in cell death and autophagy
Mrschtik, M., & Ryan, K. M. (2015) · FEBS Journal · doi:10.1111/febs.13253 · Cited by 121 · see citing works
Regulation and function of signal transducer and activator of transcription 3
Qi, Q.-R. (2014) · World Journal of Biological Chemistry · doi:10.4331/wjbc.v5.i2.231 · Cited by 114 · see citing works
Adipocyte hypertrophy and lipid dynamics underlie mammary gland remodeling after lactation
Zwick, R. K., Rudolph, M. C., Shook, B. A., Holtrup, B., Roth, E. M., Lei, V., Keymeulen, A. V., Seewaldt, V. L., Kwei, S. L., Wysolmerski, J. J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05911-0 · Cited by 110 · see citing works
Autophagy–lysosomal-associated neuronal death in neurodegenerative disease
Nixon, R. A. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02799-7 · Cited by 117 · see citing works
Faupel‐Badger, J. M., Arcaro, K. F., Balkam, J. J., Eliassen, A. H., Hassiotou, F., Lebrilla, C. B., Michels, K. B., Palmer, J. R., Schedin, P. S., Stuebe, A. M., et al. (2012) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djs505 · Cited by 110 · see citing works
Self-citationRotenone impairs autophagic flux and lysosomal functions in Parkinson’s disease
Wu, F., Xu, H., Guan, J.-J., Hou, Y., Gu, J., Zhen, X., & Qin, Z. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.11.004 · Cited by 109 · see citing works
Haim, Y., Blüher, M., Slutsky, N., Goldstein, N., Klöting, N., Harman‐Boehm, I., Kirshtein, B., Ginsberg, D., Gericke, M. T., Guiu‐Jurado, E., et al. (2015) · Autophagy · doi:10.1080/15548627.2015.1094597 · Cited by 106 · see citing works
The role of lysosome in regulated necrosis
Alu, A., Han, X., Ma, X., Wu, M., Wei, Y., & Wei, X. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.07.003 · Cited by 104 · see citing works
Lactation and Its Hormonal Control
Anderson, S., MacLean, P., McManaman, J., & Neville, M. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-397175-3.00046-6 · Cited by 68 · see citing works
Cathepsin B modulates lysosomal biogenesis and host defense against Francisella novicida infection
Qi, X., Man, S. M., Malireddi, R. K. S., Karki, R., Lupfer, C. R., Gurung, P., Neale, G. A. M., Guy, C. S., Lamkanfi, M., & Kanneganti, T. (2016) · The Journal of Experimental Medicine · doi:10.1084/jem.20151938 · Cited by 99 · see citing works
Holocrine Secretion of Sebum Is a Unique DNase2-Dependent Mode of Programmed Cell Death
Fischer, H., Fumicz, J., Rossiter, H., Napirei, M., Buchberger, M., Tschachler, E., & Eckhart, L. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.10.017 · Cited by 96 · see citing works
Aits, S., Jäättelä, M., & Nylandsted, J. (2015) · Methods in cell biology · doi:10.1016/bs.mcb.2014.10.032 · Cited by 95 · see citing works
Jessop, F., Hamilton, R. F., Rhoderick, J. F., Fletcher, P., & Holian, A. (2017) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2017.01.012 · Cited by 93 · see citing works
Overview of Mammary Gland Development: A Comparison of Mouse and Human
McNally, S., & Stein, T. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-6475-8_1 · Cited by 90 · see citing works
Cellular calcium dynamics in lactation and breast cancer: from physiology to pathology
Cross, B. M., Breitwieser, G. E., Reinhardt, T. A., & Rao, R. (2013) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00330.2013 · Cited by 90 · see citing works
Acetylation modulates the STAT signaling code
Wieczorek, M., Ginter, T., Brand, P., Heinzel, T., & Krämer, O. H. (2012) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2012.06.005 · Cited by 89 · see citing works
miR-424(322)/503 is a breast cancer tumor suppressor whose loss promotes resistance to chemotherapyPreprint
Barrueco, R. R., Nekritz, E. A., Bertucci, F., Yu, J., Sanchez-Garcia, F., Zeleke, T. Z., Gorbatenko, A., Birnbaum, D., Ezhkova, E., Cordon‐Cardo, C., et al. (2017) · Genes & Development · doi:10.1101/gad.292318.116 · Cited by 87 · see citing works
The Multifaceted Role of STAT3 in Mammary Gland Involution and Breast Cancer
Hughes, K., & Watson, C. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19061695 · Cited by 69 · see citing works
Self-citationWatson, C. J., & Khaled, W. T. (2020) · Development · doi:10.1242/dev.169862 · Cited by 84 · see citing works
Self-citationZhao, P., Yin, S., Qiu, Y., Sun, C., & Yu, H. (2025) · Molecular Cancer · doi:10.1186/s12943-024-02217-2 · Cited by 90 · see citing works
HDAC8 and STAT3 repress BMF gene activity in colon cancer cells
Kang, Y., Nian, H., Rajendran, P., Kim, E., Dashwood, W. M., Pinto, J. T., Boardman, L. A., Thibodeau, S. N., Limburg, P. J., Löhr, C. V., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.422 · Cited by 83 · see citing works
Yuan, X., Nie, W., He, Z., Yang, H. J., Shao, B., Ma, X., Zhang, X., Bi, Z., Sun, L., Liang, X., et al. (2020) · Theranostics · doi:10.7150/thno.34065 · Cited by 82 · see citing works
Martínez‐Fábregas, J., Prescott, A. R., van Kasteren, S. I., Pedrioli, D. M. L., McLean, W. H. I., Moles, A., Reinheckel, T., Poli, V., & Watts, C. K. W. (2018) · Nature Communications · doi:10.1038/s41467-018-07741-6 · Cited by 81 · see citing works
Self-citationLysosomal membrane homeostasis and its importance in physiology and disease
Radulovic, M., Yang, C., & Stenmark, H. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00873-w · Cited by 86 · see citing works
Hsp70.1 and related lysosomal factors for necrotic neuronal death
Yamashima, T. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07596.x · Cited by 78 · see citing works
Aizawa, S., Brar, G., & Tsukamoto, H. (2019) · Gut and Liver · doi:10.5009/gnl18486 · Cited by 77 · see citing works
Arnandis, T., Vicens, I. F., García–Trevijano, E. R., Miralles, V. J., García, C., Torres, L., Vinã, J. R., & Zaragozá, R. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.46 · Cited by 76 · see citing works
EGF-mediated induction of Mcl-1 at the switch to lactation is essential for alveolar cell survival
Fu, N. Y., Rios, A. C., Pal, B., Soetanto, R., Lun, A. T. L., Liu, K., Beck, T. J., Best, S. A., Vaillant, F., Bouillet, P., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3117 · Cited by 75 · see citing works
Hughes, K., & Watson, C. J. (2018) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-018-9395-1 · Cited by 75 · see citing works
Self-citationNucleus, mitochondrion, or reticulum? STAT3 à La Carte
Avalle, L., & Poli, V. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092820 · Cited by 74 · see citing works
Self-citationTuzlak, S., Kaufmann, T., & Villunger, A. (2016) · Genes & Development · doi:10.1101/gad.289298.116 · Cited by 73 · see citing works
Deng, H., Yang, Z., Pang, X., Zhao, C., Tian, J., Wang, Z., & Chen, X. S. (2021) · Nano Today · doi:10.1016/j.nantod.2021.101337 · Cited by 73 · see citing works
The role of lysosome in cell death regulation
Yu, F., Chen, Z., Wang, B., Zhao, J., Hou, Y., Ma, S., & Liu, X. (2015) · Tumor Biology · doi:10.1007/s13277-015-4516-6 · Cited by 72 · see citing works
Kim, H., Zamel, R., Bai, X.-H., Lu, C., Keshavjee, S., Keshavjee, S. H., & Liu, M. (2018) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00069.2018 · Cited by 69 · see citing works
Non-apoptotic cell death in animal development
Kutscher, L. M., & Shaham, S. (2017) · Cell Death & Differentiation · doi:10.1038/cdd.2017.20 · Cited by 67 · see citing works
Kim, A., & Cunningham, K. W. (2015) · Molecular Biology of the Cell · doi:10.1091/mbc.e15-08-0581 · Cited by 67 · see citing works
The Role of Cathepsin B in Pathophysiologies of Non-tumor and Tumor tissues: A Systematic Review
Wang, J., Zheng, M., Yang, X., Zhou, X., & Zhang, S. (2023) · Journal of Cancer · doi:10.7150/jca.86531 · Cited by 66 · see citing works
Liu, X., Yang, W., Guan, Z.-Z., Yu, W., Fan, B., Xu, N., & Liao, D. J. (2018) · Cell & Bioscience · doi:10.1186/s13578-018-0206-6 · Cited by 64 · see citing works
The mTOR–lysosome axis at the centre of ageing
Carosi, J. M., Fourrier, C., Bensalem, J., & Sargeant, T. J. (2021) · FEBS Open Bio · doi:10.1002/2211-5463.13347 · Cited by 66 · see citing works
Targeting of Rac GTPases blocks the spread of intact human breast cancer
Katz, E., Sims, A. H., Sproul, D., Caldwell, H., Dixon, J. M., Meehan, R. R., & Harrison, D. J. (2012) · Oncotarget · doi:10.18632/oncotarget.520 · Cited by 62 · see citing works
Autophagy-dependent versus autophagy-independent ferroptosis
Zhu, Y., Fujimaki, M., & Rubinsztein, D. C. (2025) · Trends in Cell Biology · doi:10.1016/j.tcb.2025.01.005 · Cited by 63 · see citing works
Lage, S. L., Buzzo, C. D. L., Amaral, E. P., Matteucci, K. C., Massis, L. M., Icimoto, M. Y., Carmona, A. K., Lima, M. R. D., Rodrigues, M. M., Ferreira, L. C. D. S., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1305316110 · Cited by 61 · see citing works
The spectrum of STAT functions in mammary gland development
Hughes, K., & Watson, C. J. (2012) · JAK-STAT · doi:10.4161/jkst.19691 · Cited by 60 · see citing works
Self-citationTFEB-mediated lysosomal exocytosis alleviates high-fat diet–induced lipotoxicity in the kidney
Nakamura, J., Yamamoto, T., Takabatake, Y., Namba‐Hamano, T., Minami, S., Takahashi, A., Matsuda, J., Sakai, S., Yonishi, H., Maeda, S., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.162498 · Cited by 59 · see citing works
Burton, L. J., Smith, B. A., Smith, B., Loyd, Q., Nagappan, P., McKeithen, D. N., Wilder, C. L., Platt, M. O., Hudson, T., & Odero-Marah, V. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv084 · Cited by 59 · see citing works
The Stat3 paradox: A killer and an oncogene
Resemann, H. K., Watson, C. J., & Lloyd‐Lewis, B. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.06.029 · Cited by 58 · see citing works
Self-citationMammary Gland Involution as an Immunotherapeutic Target for Postpartum Breast Cancer
Fornetti, J., Martinson, H. A., Betts, C. B., Lyons, T. R., Jindal, S., Guo, Q., Coussens, L. M., Borges, V. F., & Schedin, P. S. (2014) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-014-9322-z · Cited by 57 · see citing works
Mechanism and preclinical prevention of increased breast cancer risk caused by pregnancy
Haricharan, S., Dong, J., Hein, S., Reddy, J. P., Du, Z., Toneff, M. J., Holloway, K. R., Hilsenbeck, S. G., Huang, S., Atkinson, R. L., et al. (2013) · eLife · doi:10.7554/elife.00996 · Cited by 55 · see citing works
EGFR-mediated apoptosis via STAT3
Jackson, N. M., & Ceresa, B. P. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.04.016 · Cited by 55 · see citing works
Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle
Marques, A. R. A., Ramos, C., Machado-Oliveira, G., & Vieira, O. V. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.658995 · Cited by 52 · see citing works
- Authors
- Kreuzaler, P. A., Staniszewska, A. D., Li, W., Omidvar, N., Kedjouar, B., Turkson, J., Poli, V., Flavell, R. A., Clarkson, R. W. E., & Watson, C. J.
- Affiliations
- University of Cambridge (GB)
- Cardiff University (GB)
- University of Central Florida (US)
- University of Turin (IT)
- Yale University (US)
- Corresponding author
- Watson, Christine J.
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2011-02-20
- Volume
- 13
- Issue
- 3
- Pages
- 303-309
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2142626890
- Cited by
- 312
- References
- 44
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 18 · 2023: 18 · 2022: 16 · 2021: 19 · 2020: 24 · 2019: 16 · 2018: 30 · 2017: 14 · 2016: 23 · 2015: 24 · 2014: 27 · 2013: 27 · 2012: 22
- FWCI
- 11.03
- Type
- journal article
- Language
- en
- Open access
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Journal of International Crisis and Risk Communication Research (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Biotechnology and Biological Sciences Research Council (BB/C006836/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- STAT3, lysosomal membrane permeabilization, mammary gland involution, cathepsin B, cathepsin L, caspase-independent cell death, mammary epithelium, physiological cell death
- MeSH terms
- Animals, Cathepsin B, Cathepsins, Cell Membrane Permeability, Crosses, Genetic, Female, Gene Expression Regulation, Immunohistochemistry, Lysosomes, Mice, Inbred C57BL, Neoplasms, Mammary Neoplasms, Animal, Cell Death, STAT3 Transcription Factor, Mice, Cathepsin L
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
