Interference No. 104,436 Paper 98
Shyarnalit v. 11illman Page 12
[89] The Xia article" [ 1008] was published in 1995.
[90] Xia is the paper McLaughlin cites for the proposition that p38 is "implicated in the apoptosis of
neurons upon growth factor removal".
[91] Xia confums that the "processes of both cell survival and cell death involve highly regulated
signaling pathways that are currently the subject of intense investigation" [1008 at 1326].
[92] Xia reports that as of 1995 many proteins had been identified that prevent or induce apoptosis
[1008 at 1326].
[931 Yja confirms that p38 was known to have a role in apoptosis in response to environmental
stresses, but that its precise function was unknown [1008 at 1326].
[94] Xia tested the effect of p38 activation apart from the activation of a different kinase by
modulating the expression of variant MKK3 enzymes, which specifically activate p38 and
concluded that MKK3 activation of p38 is sufficient to induce apoptosis [ 1008 at 1328-30].
[95] Xia concluded, however, that the field was still wide open to further study [ 1008 at 13301:
Because there are many mechanisms for the regulation of the relevant MAP
kinase pathways and various forms of cross talk between these signal transduction
pathways probably exist, the decision for cellular life or death may depend on the
integration of multiple signals. It is possible that the mechanisms proposed here
function generally in the control of apoptosis in both neuronal and non-neuronal
cells.
[961 The Raingeaud article"' [1009] was published in March 1996.
13 7- Yja, M. Dickens, J. Rainpaud, RJ. Davis & ME. Greenberg, "Opposing Effects of ERK and JNK-p38
MAP Yinases on Apoptosis", 270 Science 1326 (24 Nov. 1995) (Xia). The authors are with Harvard Medical School or
the Howard Hughes Medical Institute and the University of Massachusetts Medical School.
14 J. Raingeaud, AJ. Whitmarsh, T. Barrett, B. D6rijard & RJ. Davis, "MKK3- and MKK6-Regulated Gene
Expression Is Mediated by the p38 Mitogen-Activated Protein Kinase Signal Transduction Pathway", 16 Mol. & Cellul
fli2L 1247 (Mar. 1996) (Raingeaud). Tle authors are with the Howard Hughes Institute and the University of
Massachusetts Medical School. Two also appear on the Xia paper.
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