Role of stress-activated protein kinase p38MAPK in human diseases

ACuenda

 

Ana Cuenda

Group Leader

Contact

Research summary

The aim of our group is to understand the role of p38MAPK proteins in physiology and disease. They regulate diverse cellular functions in normal conditions and in response to environmental stress, infection and proinflammatory cytokines. Moreover, they become deregulated in several human disease situations such as oncogenic transformation and inflammation, making them promising targets for new therapeutic avenues.


 

 

Publications

Alsina‐Beauchamp D, Escós A, Fajardo P, González‐Romero D, E Díaz‐Mora, Risco A, Martín‐Serrano MA, del Fresno C, Dominguez‐Andrés J, Aparicio N, Zur R, Shpiro N, Brown GD, Ardavín C, Netea MG, Alemany S, Sanz‐Ezquerro JJ, Cuenda A. Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity. EMBO Mol Med 2018; e8485; DOI 10.15252/emmm.201708485.

Risco A, Martin-Serrano MA, Barber DF, Cuenda A. p38γ and p38δ Are Involved in T Lymphocyte Development. Front Immunol. 2018 Jan 29;9:65. doi: 10.3389/fimmu.2018.00065. eCollection 2018.

Cuenda A, Sanz-Ezquerro JJ. p38γ and p38δ: From Spectators to Key Physiological Players. Trends Biochem Sci. 2017; 42(6):431-442

Zur R, Garcia-Ibanez L, Nunez-Buiza A, Aparicio N, Liappas G, Escós A, Risco A, Page A, Saiz-Ladera C, Alsina-Beauchamp D, Montans J, Paramio JM, Cuenda A. Combined deletion of p38γ and p38δ reduces skin inflammation and protects from carcinogenesis. Oncotarget. 2015 May 30;6(15):12920-35

Del Reino P, Alsina-Beauchamp D, Escós A, Cerezo-Guisado MI, Risco A, Aparicio N, Zur R, Fernandez-Estévez M, Collantes E, Montans J, Cuenda A. Pro-oncogenic role of alternative p38 mitogen-activated protein kinases p38γ and p38δ, linking inflammation and cancer in colitis-associated colon cancer. Cancer Res. 2014 Nov 1;74(21):6150-60. doi: 10.1158/0008-5472.CAN-14-0870.

 

Figure 1

The aim of our research is to determine the physiological and pathological functions of the p38MAPK family in the context of inflammatory diseases and cancer. We hope that our findings will enable us to design new strategies to treat these diseases.

Our laboratory is focused on:

  •  the study of p38MAPKs as a link between chronic inflammation and cancer, and as mediators of inflammatory diseases, and
  •  the discovery of new substrates, interacting proteins and inhibitors for these kinases, as a mean to understand their biological and physiological roles.

Inflammation stands at the centre of many pathological (cancer) and natural (tissue repair) processes. It is well known that, in the right place and at the right time, it controls a healthy host response, but uncontrolled inflammation can cause disease. We want to expand our knowledge of the molecular mechanisms involved in the inflammatory response in the settings of: 1) chronic inflammation leading to tumour development (as in colon cancer associated to colitis); 2) infection, and 3) tissue repair/regeneration.

Our studies utilize biochemical, cell biology as well as whole animal model approaches using the genetically modified mice we have generated.

We have discovered that alternative p38MAPK (p38γ and p38δ) play essential roles in the control of the inflammatory response in diverse models of disease and that they are potential targets for the discovery of new drug to treat human pathologies.

In a systemic candidiasis model we have shown that p38γ/p38δ deletion protects against Candida albicans infection and increases mice survival. C. albicans is normally a benign member of the microbiota that colonize the gastrointestinal tract. p38γ/p38δ-/- mice exhibit increased fungicidal activity and decreased systemic inflammation. We also defined a novel Dectin-1 signalling pathway by which p38γ and p38δ are essential for ERK pathway activation and contribute to production of inflammatory cytokines in macrophages infected by C. albicans. We demonstrated that genetic and chemical inhibition of p38γ/p38δ reduce mice fungal burden, establishing p38γ/p38δ as therapeutic targets in humans.

In the collagen-induced arthritis model of chronic inflammation, we showed that combined p38γ and p38δ deficiency markedly reduced synovial inflammation and bone destruction. Reduced arthritis severity in p38γ/δ-null mice was associated with lower cytokine production, T cell proliferation and anti-collagen antibody responses than in controls, indicating that p38γ and p38δ are crucial regulators of inflammatory joint destruction in CIA. We proposed p38γ and p38δ as potential therapeutic targets in complex diseases, such as rheumatoid arthritis, that involve innate and adaptive immune responses.

Chronic inflammation is a known risk factor for tumourigenesis. We analysed the role of p38γ and p38δ in skin cancer and in colitis-associated colon cancer (CAC). We found that p38γ/δ deficiency decreased tumour formation significantly in both models, in parallel with decreased production of proinflammatory cytokines and chemokines. In the case of CAC, analysis of leukocyte populations in p38γ/δ-null mouse colon showed less macrophage and neutrophil recruitment than in WT mice. The generation of chimeric mice by bone marrow transplantation determined that p38γ/p38δ in the hematopoietic compartment control tumour development in the colon. Our results establish that p38γ and p38δ are central to colon inflammation-induced tumour formation, and validate these p38MAPKs as potential targets for cancer therapy.

 

Figure 2

 418GrupoACuenda2 

Name
Position
Contact
Ana Cuenda Principal investigator
Ana Risco Postdoctoral scientist
Alejandra Escós Predoctoral scientist
Miguel Angel Martín Predoctoral scientist
Diego González Romero Predoctoral scientist
Pilar Fajardo Flores Predoctoral scientist
Ester Díaz Mora Predoctoral scientist
José Martín Gómez Predoctoral scientist
Ruth Gómez-Caro Technician
Elena Fernández Cortés Navia Technician

NOTE! This site uses cookies and similar technologies.

If you continue browsing or do not change browser settings, we consider your acepptance for using. Learn more

I understand

COOKIES POLICY

A cookie is a text file that is stored on your computer or mobile device via a web server and only that server will be able to retrieve or read the contents of the cookie and allow the Web site remember browser preferences and navigate efficiently. Cookies make the interaction between the user and the website faster and easier.

General information

This Website uses cookies. Cookies are small text files generated by the web pages you visit, which contain the session data that can be useful later in the website. In this way this Web remembers information about your visit, which can facilitate your next visit and make the website more useful.

How do cookies?

Cookies can only store text, usually always anonymous and encrypted. No personal information is ever stored in a cookie, or can be associated with identified or identifiable person.

The data allow this website to keep your information between the pages, and also to discuss how to interact with the website. Cookies are safe because they can only store information that is put there by the browser, which is information the user entered in the browser or included in the page request. You can not run the code and can not be used to access your computer. If a website encrypts cookie data, only the website can read the information.

What types of cookies used?

The cookies used by this website can be distinguished by the following criteria:

1. Types of cookies as the entity that manages:

Depending on who the entity operating the computer or domain where cookies are sent and treat the data obtained, we can distinguish:

- Own cookies: are those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which provides the service requested by the user.

- Third party cookies: these are those that are sent to the user's terminal equipment from a machine or domain that is not managed by the publisher, but by another entity data is obtained through cookies.

In the event that the cookies are installed from a computer or domain managed by the editor itself but the information collected by these is managed by a third party can not be considered as party cookies.

2. Types of cookies as the length of time that remain active:

Depending on the length of time that remain active in the terminal equipment can be distinguished:

- Session cookies: cookies are a type designed to collect and store data while the user accesses a web page. Are usually used to store information that only worth preserving for the service requested by the user at any one time (eg a list of products purchased).

- Persistent cookies: cookies are a type of data which are stored in the terminal and can be accessed and treated for a period defined by the head of the cookie, and can range from a few minutes to several years.

3. Cookies types according to their purpose:

Depending on the purpose for which the data are processed through cookies, we can distinguish between:

- Technical cookies: these are those that allow the user to navigate through a web page or application platform and the use of different options or services it exist as, for example, control traffic and data communication, identify the session, access to restricted access parts, remember the elements of an order, make the buying process an order, make an application for registration or participation in an event, use security features while browsing store content for dissemination videos or sound or share content via social networks.

- Customization cookies: these are those that allow the user to access the service with some general characteristics based on a predefined set of criteria in the user terminal would eg language, the type of browser through which you access the service, the locale from which you access the service, etc.

- Analysis cookies: they are those that allow the responsible for them, monitoring and analyzing the behavior of users of the web sites that are linked. The information gathered through such cookies are used in measuring the activity of web sites, application or platform and for the profiling of user navigation of such sites, applications and platforms, in order to make improvements function data analysis how users use the service.

Management tool cookies

This Website uses Google Analytics.

Google Analytics is a free tool from Google that primarily allows website owners know how users interact with your website. Also, enable cookies in the domain of the site in which you are and uses a set of cookies called "__utma" and "__utmz" to collect information anonymously and reporting of website trends without identifying individual users..

For statistics of use of this website use cookies in order to know the level of recurrence of our visitors and more interesting content. This way we can concentrate our efforts on improving the most visited areas and make the user more easily find what they are looking for. On this site you can use the information from your visit for statistical evaluations and calculations anonymous data and to ensure the continuity of service or to make improvements to their websites. For more details, see the link below privacy policy [http://www.google.com/intl/en/policies/privacy/]

How to manage cookies on your computer: disabling and deleting cookies

All Internet browsers allow you to limit the behavior of a cookie or disable cookies within settings or browser settings. The steps for doing so are different for each browser, you can find instructions in the help menu of your browser.

If you decline the use of cookies, since it is possible thanks to the preferences menu of your browser or settings, reject, this website will continue to function properly without the use of the same.

Can you allow, block or delete cookies installed on your computer by setting your browser options installed on your computer:

- For more information about Internet Explorer click here.
- For more information on Chrome click here.
- For more information about Safari click here.
- For more information about Firefox click here.

Through your browser, you can also view the cookies that are on your computer, and delete them as you see fit. Cookies are text files, you can open and read the contents. The data within them is almost always encrypted with a numeric key corresponding to an Internet session so often has no meaning beyond the website who wrote it.

Informed consent

The use of this website on the other hand, implies that you paid your specific consent to the use of cookies, on the terms and conditions provided in this Cookies Policy, without prejudice to the measures of deactivation and removal of cookies that you can take, and mentioned in the previous section.