Maria Diaz-Meco, Ph.D.[La Jolla]
We are trying to better categorize tumor aggressiveness in order to help clinicians make more informed decisions about how to treat cancer.
Feedback on fat: p62-mTORC1-autophagy connections.
Moscat J, Diaz-Meco MT
Cell. 2011 Nov 11;147(4):724-7
p62 is a key regulator of nutrient sensing in the mTORC1 pathway.
Duran A, Amanchy R, Linares JF, Joshi J, Abu-Baker S, Porollo A, Hansen M, Moscat J, Diaz-Meco MT
Mol Cell. 2011 Oct 7;44(1):134-46
Fine tuning NF-κB: new openings for PKC-ζ.
Moscat J, Diaz-Meco MT
Nat Immunol. 2011 Jan;12(1):12-4
To aggregate or not to aggregate? A new role for p62.
Moscat J, Diaz-Meco MT
EMBO Rep. 2009 Aug;10(8):804
p62 at the crossroads of autophagy, apoptosis, and cancer.
Moscat J, Diaz-Meco MT
Cell. 2009 Jun 12;137(6):1001-4
Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-kappaB activation and invasive prostate carcinoma.
Fernandez-Marcos PJ, Abu-Baker S, Joshi J, Galvez A, Castilla EA, Cañamero M, Collado M, Saez C, Moreno-Bueno G, Palacios J, Leitges M, Serrano M, Moscat J, Diaz-Meco MT
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12962-7
Par-4 inhibits Akt and suppresses Ras-induced lung tumorigenesis.
Joshi J, Fernandez-Marcos PJ, Galvez A, Amanchy R, Linares JF, Duran A, Pathrose P, Leitges M, Cañamero M, Collado M, Salas C, Serrano M, Moscat J, Diaz-Meco MT
EMBO J. 2008 Aug 20;27(16):2181-93
The signaling adaptor p62 is an important NF-kappaB mediator in tumorigenesis.
Duran A, Linares JF, Galvez AS, Wikenheiser K, Flores JM, Diaz-Meco MT, Moscat J
Cancer Cell. 2008 Apr;13(4):343-54
Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62.
Rodriguez A, Durán A, Selloum M, Champy MF, Diez-Guerra FJ, Flores JM, Serrano M, Auwerx J, Diaz-Meco MT, Moscat J
Cell Metab. 2006 Mar;3(3):211-22
The atypical PKC-interacting protein p62 is an important mediator of RANK-activated osteoclastogenesis.
Durán A, Serrano M, Leitges M, Flores JM, Picard S, Brown JP, Moscat J, Diaz-Meco MT
Dev Cell. 2004 Feb;6(2):303-9
Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62.
Sanchez P, De Carcer G, Sandoval IV, Moscat J, Diaz-Meco MT
Mol Cell Biol. 1998 May;18(5):3069-80
The product of par-4, a gene induced during apoptosis, interacts selectively with the atypical isoforms of protein kinase C.
Díaz-Meco MT, Municio MM, Frutos S, Sanchez P, Lozano J, Sanz L, Moscat J
Cell. 1996 Sep 6;86(5):777-86
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A Macrophage NBR1-MEKK3 Complex Triggers JNK-Mediated Adipose Tissue Inflammation in Obesity.
Hernandez ED, Lee SJ, Kim JY, Duran A, Linares JF, Yajima T, Müller TD, Tschöp MH, Smith SR, Diaz-Meco MT, Moscat J
Cell Metab. 2014 Jul 15;
Maria Diaz-Meco's Research Focus
Dr. Diaz-Meco’s research focuses on defining novel signaling molecules as potential therapeutic targets for thetreatment of prostate cancer (PCa). PCa is one of the leading causes of death among men in the United States and its prevalence is on the increase in Western societies. PCa is a complex disease in its development and response to therapy, and the generation of new therapies and better diagnostic techniques will depend on increasing our understanding of the molecular basis of this disease. Prostate carcinogenesis is a multistage process that is governed by cumulative genetic and epigenetic alterations, and consists of initiation, promotion, and progression. While initiation is induced by genetic changes and is irreversible, tumor promotion and progression are long-lasting processes that are susceptible to be modulated and even reversed, thereby providing a rationale for therapeutic intervention.
Maria Diaz-Meco's Research Report
Tumor promotion is highly regulated by the interaction between initiated cells and their microenviroment, and inflammation is a frequent and important tumor promoter. In this context, there are two main areas of research in our laboratory:
- 1) the first one is focused on the study of the cooperation of tumor suppressors in PCa to define how these molecular networks operate to modulate carcinogenesis and tumor aggressiveness. Our laboratory identified Par-4, an inhibitor of the aPKCs, as a novel tumor suppressor whose loss cooperates with that of PTEN, a frequent event in PCa, to promote invasive carcinoma. Our goal is to address the molecular mechanismsunderlying this cooperation and to unravel how tumor suppressors regulate each other as a cellular safeguard mechanism to prevent tumorigenesis.
- 2) The other one is aimed at understanding how obesity-driven inflammation impacts PCa progression. There is increasing evidence suggesting that the inflammation associated with obesity could be a tumor promoter, and that chronic inflammation in the tumor microenvironment may contribute to prostate carcinogenesis. Moreover, there is mounting epidemiological evidence that links obesity to PCa progression and aggressiveness. Therefore, elucidating the molecular mechanisms whereby obesity regulates tumor progression is of paramount importance in designing new therapeutic strategies to treat PCa.
Cellular Signaling Studies
The Ras proto-oncogene is central to the control of cell growth and survival, and its oncogene form has been shown to be mutated in numerous human cancers. Previous results from our laboratory showed that inhibition of atypical protein kinase C (aPKC) impairs Ras-induced transformation, and that aPKC interacts with Ras in vitro
and in vivo
. These observations suggest that aPKCs could be important regulators of Ras function, and would be consistent with a model in which Ras, through regulation of the aPKCs and therefore NF-kB, modulates tumor cell survival. Consistent with this hypothesis, the proapoptotic regulator Par-4 binds and inhibits aPKCs, which translates into a reduction in NF-kB activity and enhanced cell death. Ras-induced transformation leads to the downregulation of Par-4 levels and the subsequent activation of aPKC and NF-kB transcriptional activity. This suggests that Par-4 depletion is a critical event in Ras-induced
Restoration by ectopic expression of Par-4 to parental levels does not modify the morphological characteristics of the Ras transformants, but it restrains growth of these tumor cells, inhibits their ability to grow in soft agar, and reduces their tumor-forming capacity in nude mice. Moreover, Par-4-/- cells display enhanced aPKC and NF-kB activities as well as reduced apoptosis. Also, Par-4-deficient mice are prone to cancer, particularly prostate intraepithelial neoplasia, which is abrogated in Par-4/aPKC double KO cells, suggesting that aPKC is a bona fide Par-4 target in cancer.
Relevance to Human Health
Collectively these results indicate that the aPKCs may be considered important intermediates in Ras-induced transformation. Currently, our group is interested in understanding the role of the aPKCs in the generation of prostate adenocarcinomas and hormone therapy resistance in these tumors.
Read about her research on Sanford-Burnham's blog
About Maria Diaz-Meco
Dr. Diaz-Meco earned a bachelor’s degree in Chemistry (1988), and her Ph.D. in Biochemistry & Molecular Biology (1991) at the University Complutense in Madrid, Spain with graduate training studies at the National Cancer Institute. In 1996, she became Assistant Professor at the Spanish Research Council and was promoted to Associate Professor in 2003. In 2006, she was recruited to the Genome Research Institute at the University of Cincinnati (UC). In 2010, she was appointed Professor of Cancer and Cellular Biology at UC. She joined Sanford-Burnham’s faculty in 2011.
Honors and Recognition
1989 Short-term Fellowship from the Foundation for Advanced Education in Sciences (NIH) to work under the direction of Dr. Aaronson, National Institutes of Health, Bethesda, USA.
1989 Short-term Fellowship from “Comunidad de Madrid” for the same studies in the NIH
1990-1994 Postgraduate Fellowship from the Spanish Education and Science Ministry
1990 Short-term Fellowship from “Comunidad de Madrid” to continue the studies under the direction of Dr. Aaronson, National Institutes of Health, Bethesda, USA