Matthew Pando

Salk Institute, La Jolla, CA, United States

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Publications (7)70.1 Total impact

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    ABSTRACT: Chemotherapeutic agents simultaneously induce transcription factors p53 and NFkappaB. p53 induction can activate an apoptotic program, and resistance to chemotherapy correlates with the loss of a functional p53 pathway. By contrast, NFkappaB prevents apoptosis in response to chemotherapeutic agents. We have analyzed the p53 response in IKK1/2(-/-) MEFs, which lack detectable NFkappaB activity. Compared to WT fibroblasts, IKK1/2(-/-) fibroblasts showed increased cell death and p53 induction in response to the chemotherapeutic agent, doxorubicin. Reconstitution of IKK2, but not IKK1, increased Mdm2 levels and decreased doxorubicin-induced p53 stabilization and cell death. IKK2-mediated effects required its kinase function and were abrogated by coexpression of the dominant negative IkappaBalphaM, implying a role for NFkappaB in blocking chemotherapy-induced p53 and cell death.
    Cancer Cell 07/2002; 1(5):493-503. · 23.89 Impact Factor
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    ABSTRACT: Chemotherapeutic agents simultaneously induce transcription factors p53 and NFκB. p53 induction can activate an apoptotic program, and resistance to chemotherapy correlates with the loss of a functional p53 pathway. By contrast, NFκB prevents apoptosis in response to chemotherapeutic agents. We have analyzed the p53 response in IKK1/2−/− MEFs, which lack detectable NFκB activity. Compared to WT fibroblasts, IKK1/2−/− fibroblasts showed increased cell death and p53 induction in response to the chemotherapeutic agent, doxorubicin. Reconstitution of IKK2, but not IKK1, increased Mdm2 levels and decreased doxorubicin-induced p53 stabilization and cell death. IKK2-mediated effects required its kinase function and were abrogated by coexpression of the dominant negative IκBαM, implying a role for NFκB in blocking chemotherapy-induced p53 and cell death.
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    ABSTRACT: Summary Chemotherapeutic agents simultaneously induce transcription factors p53 and NFB. p53 induction can activate an apo- ptotic program, and resistance to chemotherapy correlates with the loss of a functional p53 pathway. By contrast, NFB prevents apoptosis in response to chemotherapeutic agents. We have analyzed the p53 response in IKK1/2 / MEFs, which lack detectable NFB activity. Compared to WT fibroblasts, IKK1/2 / fibroblasts showed increased cell death and p53 induction in response to the chemotherapeutic agent, doxorubicin. Reconstitution of IKK2, but not IKK1, increased Mdm2 levels and decreased doxorubicin-induced p53 stabilization and cell death. IKK2-mediated effects required its kinase function and were abrogated by coexpression of the dominant negative IBM, implying a role for NFB in blocking chemotherapy-induced p53 and cell death.
    Cancer Cell 06/2002; 1(5):493-503. · 23.89 Impact Factor
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    ABSTRACT: Fanconi anemia (FA), a genetic disorder predisposing to aplastic anemia and cancer, is characterized by hypersensitivity to DNA-damaging agents and oxidative stress. Five of the cloned FA proteins (FANCA, FANCC, FANCE, FANCF, FANCG) appear to be involved in a common functional pathway that is required for the monoubiquitination of a sixth gene product, FANCD2. Here, we report that FANCA associates with the IkappaB kinase (IKK) signalsome via interaction with IKK2. Components of the FANCA complex undergo rapid, stimulus-dependent changes in phosphorylation, which are blocked by kinase-inactive IKK2 (IKK2 K > M). When exposed to mitomycin C, cells expressing IKK2 K > M develop a cell cycle abnormality characteristic of FA. Thus, FANCA may function to recruit IKK2, thus providing the cell a means of rapidly responding to stress.
    Journal of Cellular Biochemistry 01/2002; 86(4):613-23. DOI:10.1002/jcb.10270 · 3.37 Impact Factor
  • M P Pando · I M Verma
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    ABSTRACT: A family of inhibitory IkappaB molecules regulates the activation of the transcription factor NF-kappaB. One member of the IkappaB family, IkappaBalpha, plays a major role in the rapid signal-induced activation of NF-kappaB. IkappaBalpha itself is transcriptionally regulated by NF-kappaB allowing for a tight autoregulatory loop that is both sensitive to and rapidly influenced by NF-kappaB activating stimuli. For this pathway to remain primed both for rapid activation of NF-kappaB in the presence of signal and then to suppress NF-kappaB activation once that signal is removed, IkappaBalpha must be exquisitely regulated. The regulation of IkappaBalpha is mainly accomplished through phosphorylation, ubiquitination, and subsequent degradation. The mechanism(s) that regulate IkappaBalpha degradation needs to be able to target IkappaBalpha for degradation in both its NF-kappaB bound and free states in the cell. In this study, we utilize a full-length IkappaBalpha mutant that is unable to associate to RelA/p65. We show that the signal-induced IkappaB kinase (IKK) phosphorylation sites on IkappaBalpha can only significantly influence the regulation of signal-dependent but not signal-independent turnover of IkappaBalpha. We also demonstrate that the constitutive carboxyl-terminal casein kinase II phosphorylation sites are necessary for the proper regulation of both signal-dependent and -independent turnover of IkappaBalpha. These findings further elucidate how the phosphorylation of IkappaBalpha influences the complex regulatory mechanisms involved in maintaining a sensitive NF-kappaB pathway.
    Journal of Biological Chemistry 08/2000; 275(28):21278-86. DOI:10.1074/jbc.M002532200 · 4.57 Impact Factor
  • Matthew P. Pando · Inder M. Verma
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    ABSTRACT: A family of inhibitory IκB molecules regulates the activation of the transcription factor NF-κB. One member of the IκB family, IκBα, plays a major role in the rapid signal-induced activation of NF-κB. IκBα itself is transcriptionally regulated by NF-κB allowing for a tight autoregulatory loop that is both sensitive to and rapidly influenced by NF-κB activating stimuli. For this pathway to remain primed both for rapid activation of NF-κB in the presence of signal and then to suppress NF-κB activation once that signal is removed, IκBα must be exquisitely regulated. The regulation of IκBα is mainly accomplished through phosphorylation, ubiquitination, and subsequent degradation. The mechanism(s) that regulate IκBα degradation needs to be able to target IκBα for degradation in both its NF-κB bound and free states in the cell. In this study, we utilize a full-length IκBα mutant that is unable to associate to RelA/p65. We show that the signal-induced IκB kinase (IKK) phosphorylation sites on IκBα can only significantly influence the regulation of signal-dependent but not signal-independent turnover of IκBα. We also demonstrate that the constitutive carboxyl-terminal casein kinase II phosphorylation sites are necessary for the proper regulation of both signal-dependent and -independent turnover of IκBα. These findings further elucidate how the phosphorylation of IκBα influences the complex regulatory mechanisms involved in maintaining a sensitive NF-κB pathway.
    Journal of Biological Chemistry 07/2000; 275(28):21278-21286. · 4.57 Impact Factor
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    ABSTRACT: The NF-kappaB/Rel proteins are sequestered in the cytoplasm in association with IkappaBalpha. In response to external signals, IkappaBalpha is phosphorylated, multi-ubiquitinated, and degraded by proteasomes, thereby releasing NF-kappaB/Rel proteins to migrate to the nucleus. We have cloned a mouse ubiquitin-conjugating enzyme (mE2), which associates with IkappaBalpha. mE2 is homologous to the yeast Ubc9/Hus5 ubiquitin-conjugating enzyme. A transdominant-negative mutant of mE2 had no effect on phosphorylation of IkappaBalpha, but delayed its degradation. Correspondingly, tumor necrosis factor-alpha-inducible NF-kappaB activity was diminished. We propose that mE2 is directly involved in the ubiquitin conjugation of IkappaBalpha, a pivotal step in its degradation pathway.
    Proceedings of the National Academy of Sciences 08/1997; 94(15):7862-7. DOI:10.1073/pnas.94.15.7862 · 9.81 Impact Factor