MECANISMOS MOLECULARES INVOLUCRADOS EN LA DIFERENCIACIN

CELULAR LEUCMICA. BSQUEDA DE NUEVOS BLANCOS TERAPUTICOS

DIRECTOR: DAVIO, CARLOS A.
FACULTAD DE FARMACIA Y BIOQUMICA
SALUD HUMANA
Las terapias actuales para el tratamiento del cncer resultan altamente txicas y no especficas. En
los ltimos aos ha surgido una estrategia menos txica que consiste en la utilizacin de agentes
inductores de diferenciacin de las clulas cancerosas, anulando su capacidad proliferativa.
Desde hace varios aos estudiamos el papel de los receptores a histamina en los procesos de
proliferacin y diferenciacin de clulas leucmicas humanas. Demostramos que la falta de accin
diferenciante de la histamina en clulas promonocticas U-937 es debida a la rpida
desensibilizacin de los receptores H2 a histamina (rH2). Este proceso es mediado por fosforilacin
del receptor, dependiente de GRK2 y 3. Recientemente, demostramos que la reduccin de la
expresin de GRK2 en clulas U-937 atena la desensibilizacin del rH2, permitiendo la
diferenciacin promovida por agonistas H2. Dada la importancia de la desensibilizacin de
receptores no slo en el corte de una seal sino tambin en la determinacin de una respuesta
como ser la diferenciacin celular, nos proponemos profundizar el estudio de este mecanismo.
Analizaremos la internalizacin y reciclado de receptores, la cascada de transduccin
independiente de protena G, la intensidad de la respuesta de AMPc y su implicancia en la
transcripcin de genes relacionados con la proliferacin y diferenciacin celular, aportando nuevos
conocimientos en el rea bsica que permitirn detectar nuevos blancos para la terapia de
diferenciacin celular.
Por otro lado, conociendo que la desregulacin de GRK2 est involucrada en numerosos procesos
patolgicos, analizaremos la relacin entre los niveles de esta quinasa y distintos tipos de
leucemias.

MOLECULAR MECHANISMS INVOLVED ON LEUKEMIA CELL

DIFFERENTIATION. APPROACH FOR NEW THERAPEUTIC TARGETS
DIRECTOR: DAVIO, CARLOS A.
SCHOOL OF PHARMACY AND BIOCHEMISTRY
HUMAN HEALTH
Current cancer therapies are highly toxic and often nonspecific. A potentially less toxic approach to
treating this disease employs agent that modify cancer cell differentiation, termed "differentiation
therapy". This approach is based on the tacit assumption that many neoplastic cell types exhibit
reversible defects in differentiation, which upon appropriate treatment, results in tumor
reprogramming and a concomitant loss in proliferative capacity and induction of terminal
differentiation.
For a long time we have been studying the role of histamine receptors on proliferation and cellular
differentiation. Concerning this, we have demonstrated that histamine was unable to differentiate
the promonocityc cell line U-937 due to H2 receptor rapid desensitization. We found that G-protein
coupled receptor kinases (GRKs) type 2 and 3 mediated phosphorylation was involved in this
phenomenon. Recently, we described that reduction of GRK2 expression in U-937 cells attenuates
H2 histamine receptor desensitization and induces cell maturation.
Since receptor desensitization shows to be involved not only in signal termination but also in the
kind of response evoked, the aim of the present work is to study deeply such mechanism. We will

analyze receptor internalization and recycling, G-protein independent pathway, cAMP response
intensity and its implications in proliferation and differentiation genes expression.
Besides, knowing that GRK2 deregulation is involved in several pathological process we will study
the relation between GRK2 levels and different leukemia's as a possible marker and/or therapeutic
target.