Interference No. 104,436 Paper 98
Shyarnala v. Hillman Page 10
[691 Subs-h-ate means a molecule on which an enzyme acts.9
[70]. Lee notes that "a number of [gene] trariscription factors are phosphorylated in vitro by p38, [but]
the physiological relevance of this phosphorylation is unknown [1005 at 391:Rl.
[71] Lee reports regarding a protein called ATF2 that [1005 at 391:R]:
[w]hile it is an excellent in vitro substrate for p38 and other isoforms, it is not
clear if ATF2 is a physiological substrate of p38a since the transcriptional
activation or phosphorylation-mediated mobility shift in ATF2 has not been
correlated yet with pharmacological inhibition of p38 MAPK.
[72] A synthetic p38 MAPK inhibitor is reported to have been used in 1998 in an in vivo model of
angiogenesis [1005 at 392:L] and in 1996 in an in vivo model of TNF-a-mediated inflarnation,
endotoxin-induced shock, arthritis, and parathyroid hormone-induced bone resorption [ 1005
at 394:L-395:R].
[73] Lee indicates that in 1999, the p38 MAPK-inhibition art was still marked by considerable
uncertainty, particularly in translating in vitro suggestions into in vivo results, and was only just
beginning to bear therapeutic fruit for one of a class of synthetic p38 kinase inhibitors.
[74] The McLaughlin article" [1006] was published on 5 April 1996.
[75] According to McLaughlin, CSBP is a synonym for p38 [1006 at 8488:R].
[76] According to Herlaar, by 1999 CSBP was associated with one isoform of p38 [1004, Table 1].
[77] McLaughlin reports that p38 is activated by MKK3 and MKK4 in response to stress and
activated by a number of other environmental factors, including TNF [1006 at 8488:Rj.
9 B. Alberts et al., Molecular Biology of the Cell at G-22 (3d ed. 1994).
10 M.M. McLaughlin et al., "Identification of Mitogen-activated Protein (MAP) Vinase-activated Protein
Kinase-3, a Novel Substrate of CSBP p38 MAP Vinase", 271 J. Biol. Chem. 8488 (1996) (McLaughlin). The authors are
with Sinith)(line Beecham Pharmaceuticals. Two of the authors are also listed as authors on the Lee article.
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